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Query Topic: ABL1

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acute lymphoblastic leukemia(203)

Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia with e1a3 BCR-ABL1 transcript in a Nigerian with sickle cell anemia: a case report.
The occurrence of acute leukemia in patients with sickle cell anemia is uncommon. The Philadelphia chromosome is the hallmark of chronic myeloid leukemia. However, it may also be associated with acute lymphoblastic leukemia and acute myeloblastic leukemia. The common BCR-ABL1 transcripts seen in acute lymphoblastic leukemia are e1a2, e13a2, and e14a2, while other transcripts such as e1a3, e13a3, and e6a2 occur rarely. This report describes the presentation, management, and outcome of the occurrence of B-cell acute lymphoblastic leukemia with the rare e1a3 BCR-ABL1 transcript in a patient with sickle cell anemia. A 19-year-old male Nigerian, a known sickle cell anemia patient was admitted on account of severe vaso-occlusive crisis. Examination revealed fever, palor, and jaundice. Full blood count showed anemia and leukocytosis. Peripheral blood and bone marrow smears revealed numerous large and small lymphoblasts in keeping with the L2 subtype of acute lymphoblastic leukemia based on the French-American-British classification. Further evaluation was in keeping with a diagnosis of BCR-ABL1-positive mature B-cell acute lymphoblastic leukemia associated with the rare e1a3 transcript. He was commenced simultaneously on induction chemotherapy and Imatinib while being prepared for allogeneic stem cell transplantation. However, he died  six  months after diagnosis from meningoencephalitis. The occurrence of acute lymphoblastic leukemia with a rare BCR-ABL1 e1a3 transcript in association with sickle cell anemia is uncommon and associated with poor prognosis.
Publication Date: 2021-10-10
Journal: Journal of medical case reports

tyrosine kinase inhibitor(141)

Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing
Ponatinib is a tyrosine kinase inhibitor (TKI) directed against BCR-ABL1 which is successfully used in patients with
Publication Date: 2021-10-19
Journal: American journal of cancer research

bcr-abl1 tyrosine kinase(129)

The cure of leukemia through the optimist's prism.
Progress is occurring at a dizzying rate across all leukemias. Since the authors' review of the topic in Cancer in 2018, numerous discoveries have been made that have improved the therapy and outcomes of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab (10-year survival, ≥90%). Acute promyelocytic leukemia is curable at a rate of 80% to 90% with a nonchemotherapy regimen of all-trans retinoic acid and arsenic trioxide. The cure rate for core-binding factor acute myeloid leukemia (AML) is ≥75% with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin. Survival for patients with chronic myeloid leukemia is close to that for an age-matched normal population with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Chronic lymphocytic leukemia, a previously incurable disease, may now be potentially curable with a finite duration of therapy with Bruton tyrosine kinase inhibitors and venetoclax. The estimated 5-year survival rate for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) exceeds 70% with intensive chemotherapy and ponatinib, a third-generation BCR-ABL1 TKI, and more recent nonchemotherapy regimens using dasatinib or ponatinib with blinatumomab are producing outstanding results. Survival in both younger and older patients with ALL has improved with the addition of antibodies targeting CD20, CD19 (blinatumomab), and CD22 (inotuzumab) to chemotherapy. Several recent drug discoveries (venetoclax, FLT3 and IDH inhibitors, and oral hypomethylating agents) are also improving outcomes for younger and older patients with AML and for those with higher risk myelodysplastic syndrome.
Publication Date: 2021-10-07
Journal: Cancer

chronic myelogenous leukemia(107)

Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells.
It is well known that mature chronic myelogenous leukemia (CML) cells proliferate in response to oncogenic BCR-ABL1-dependent signaling, but how CML stem cells are able to survive in an oncogene-independent manner and cause disease relapse has long been elusive. Here, I put into the context of the broader literature our recent finding that lysophospholipid metabolism is essential for the maintenance of CML stem cells. I describe the fundamentals of lysophospholipid metabolism and discuss how one of its key enzymes, Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3), is responsible for maintaining the unique characteristics of CML stem cells. I also explore how this knowledge may be exploited to devise novel therapies for CML patients.
Publication Date: 2021-07-25
Journal: Cancers

chronic myeloid leukaemia(91)

BCR/ABL1-positive histiocytic sarcoma of the small intestine in a patient with chronic myeloid leukaemia.
Histiocytic sarcoma (HS) is a rare myeloid-derived neoplasm with histiocytic differentiation and an aggressive clinical course. Recent studies suggest a common clonal origin between various haematolymphoid disorders. However, HS coexisting with chronic myeloid leukaemia (CML) without tyrosine kinase inhibitors (TKIs) has not been reported.
Publication Date: 2021-09-09
Journal: Histopathology

polymerase chain reaction(78)

BCR-ABL1 transcript doubling time as a predictor for treatment-free remission failure after imatinib discontinuation in chronic myeloid leukaemia in chronic phase.
The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.
Publication Date: 2021-09-09
Journal: British journal of haematology

bcr-abl1 kinase domain(63)

The role of E255K/V-inclusive mutations in a Philadelphia-positive acute lymphoblastic leukemia with mutation evolution during sequential TKIs therapies: A case report.
Until recently, the survival rate in patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) was approximately 30%. Tyrosine kinase inhibitors (TKIs), which are a new class of drugs that target BCR-ABL fusion protein, have shown to be effective in treating Ph+ ALL in adults. However, the resistance mechanisms that promote the disease recurrence have altered the initial success of these revolutionary agents. A 71-year-old Chinese female patient who suffered from severe shoulder and back pain for 1 week. The patient was diagnosed with Ph+ ALL (B-cell) because of the following items. Complete blood count showed extremely abnormal white blood cell count (26.26×109/l), hemoglobin concentration (65 g/l) and platelet count (14×109/l). And because that Bone marrow aspirate showed 72.5% lymphoblasts and 59.30% lymphoblasts were confirmed by flow cytometry (FCM). At mean time, Real-time fluorescent quantitative PCR analysis confirmed that the P190 BCR/ABL fusion gene expression was 5.9%. Karyotype analysis indicated the following: 45, XX, -7, t (922) (q34; q11) [cp3]. The patient was treated with chemotherapy and different TKIs including imatinib, dasatinib, ponatinib, and bosutinib. The patient achieved complete remissions with different TKIs after diagnose but relapsed afterward and died of infection. Multidrug-resistant mutations within the BCR-ABL1 kinase domain are an emerging clinical problem for patients receiving sequential TKIs therapy. Acquisition of E255K/V-inclusive mutations is usually associated with ponatinib resistance, thus it is necessary to screen out new real pan-inhibitor compounds for all BCR/ABL mutations and figure out the potential efficacy of asciminib-based drug combinations in the future.
Publication Date: 2021-05-06
Journal: Medicine

bcr abl1 fusion(58)

DNA index as prognostic factor in childhood acute lymphoblastic leukemia in the COG-TARGET database.
This study was aimed to evaluate the value of DNA index(DI) among pediatric acute lymphoblastic leukemia (ALL) treated on Children's Oncology Group (COG) protocols between 2000 and 2015. Retrospective study were analysis among pediatric ALL patients from the TARGET dataset. Totally, 1668 eligible pediatric patients were enrolled in this study. Of them, 993 are male and 675 are female with a median age of 7.6 years old. The median follow-up for those patients was 7.7 years (range 0.1-15.7 years). The probability of 15-year EFS and OS were reported to be 67.5 ± 3.1% and 78.3 ± 2.5%, respectively. BCR/ABL1 fusion gene affected the early treatment response and the survival of childhood ALL. Moreover, those patients with ETV6/RUNX1 fusion gene were also significantly associated with better EFS (HR = 0.6, 95% CI 0.4-0.8, P = 0.003) and OS (HR = 0.3, 95%CI 0.2-0.5, P < 0.001) compared to patients with no ETV6/RUNX1. On the contrary, BM NR on Day+ 29 showed a significant decrease in EFS (HR = 3.1, 95%CI 2.1-4.5, P < 0.001) and OS (HR = 1.7, 95%CI 1.1-2.8, P = 0.026). Multivariate analysis showed that DI was significantly associated with better EFS and OS. The threshold effect of DI on poor outcome was significant after adjusting for potential confounders. The adjusted regression coefficient (Log RR) was 0.7 (95%CI 0.1-3.2, P = 0.597) for DI < 1.1 while 8.8 (95%CI 1.4-56.0, P = 0.021) for DI ≥ 1.2 and 0.0 (95%CI 0.0-0.8, P = 0.041) for 1.1 ≤ DI < 1.2. Generalized additive models revealed that the lowest rates of the adverse outcomes estimated to occur among DI between 1.1 and 1.2. For those childhood ALL treated on COG protocols between 2000 and 2015, ETV6/RUNX1 and BM NR were closely related to the prognosis. Moreover, the DI between 1.1 and 1.2 can serve as a significant cut-point discriminating the risk group, which indicated a favourable prognostic factor.
Publication Date: 2021-07-17
Journal: BMC cancer

major molecular response(47)

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.
Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients. To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML. The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020. Discontinuation of TKIs. Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR). Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs. In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies. Identifier: NCT02269267.
Publication Date: 2020-11-13
Journal: JAMA oncology

kinase domain mutations(47)

Hierarchical distribution of somatic variants in newly diagnosed chronic myeloid leukaemia at diagnosis and early follow-up.
There is an emerging body of evidence that patients with chronic myeloid leukaemia (CML) may carry not only breakpoint cluster region-Abelson murine leukaemia viral oncogene homologue 1 (BCR-ABL1) kinase domain mutations (BCR-ABL1 KD mutations), but also mutations in other genes. Their occurrence is highest during progression or at failure, but their impact at diagnosis is unclear. In the present study, we prospectively screened for mutations in 18 myeloid neoplasm-associated genes and BCR-ABL1 KD in the following populations: bulk leucocytes, CD34
Publication Date: 2021-07-03
Journal: British journal of haematology

acute myeloid leukemia(46)

Solving the Puzzle: The Diagnosis of Atypical Chronic Myeloid Leukemia, BCR-ABL1-Negative (aCML).
Atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML), is a rare myelodysplastic/myeloproliferative neoplasm with heterogeneous clinical and genetic features, a high rate of transformation to acute myeloid leukemia (AML), and poor survival rate. The diagnosis of aCML is a diagnosis of exclusion and requires the fulfillment of strict diagnostic criteria. Until recently, there were no distinctive cytogenetic or molecular abnormalities for aCML adding to the diagnostic challenge. We present a case of aCML and highlight the pertinent clinical, morphological, and genetic features required for the diagnosis.
Publication Date: 2021-09-08
Journal: Journal of the Association of Genetic Technologists

bcr-abl1 transcript levels(43)

Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts: recommendations by the EUTOS cooperative network.
Approximately 1-2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). In total, 330 blood samples (2-34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.
Publication Date: 2021-03-08
Journal: Journal of cancer research and clinical oncology

q34 q11 2(42)

From the archives of MD Anderson Cancer Center: Concurrent BCR-ABL1 and CRLF2 rearrangements in B-lymphoblast phase of chronic myeloid leukemia.
The t(9;22)(q34;q11.2), also known as the Philadelphia (Ph) chromosome, results in BCR-ABL1 fusion residing on the derivative chromosome 22. This translocation is characteristic of chronic myeloid leukemia, but also can occur in a substantial subset of B acute lymphoblastic leukemia (B-ALL) cases. Ph-like B-ALL has a gene expression profile similar to that of BCR-ABL1 positive/Ph-positive B-ALL, but by definition Ph-like B-ALL does not have the sentinel BCR-ABL1 or the Ph chromosome. About half of Ph-like B-ALL cases carry CRLF2 rearrangements. Rare cases of de novo B-ALL with co-occurrence of BCR-ABL1 and CRLF2 rearrangements have been described. To our knowledge, this is the first report of concurrent BCR-ABL1 and CRLF2 rearrangements in blast phase of chronic myeloid leukemia. In this patient, CRLF2 rearrangement was acquired at the time of disease progression to B-lymphoblast phase of chronic myeloid leukemia. We also review the literature and discuss the distinct clinicopathologic, and genomic characteristics of CRLF2 rearranged B-ALL.
Publication Date: 2021-06-13
Journal: Annals of diagnostic pathology

breakpoint cluster region(34)

MiR-125a-3p and MiR-320b Differentially Expressed in Patients with Chronic Myeloid Leukemia Treated with Allogeneic Hematopoietic Stem Cell Transplantation and Imatinib Mesylate.
Chronic myeloid leukemia (CML), a hematopoietic neoplasm arising from the fusion of BCR (breakpoint cluster region) gene on chromosome 22 to the ABL (Abelson leukemia virus) gene on chromosome 9 (BCR-ABL1 oncogene), originates from a small population of leukemic stem cells with extensive capacity for self-renewal and an inflammatory microenvironment. Currently, CML treatment is based on tyrosine kinase inhibitors (TKIs). However, allogeneic hematopoietic stem cell transplantation (HSCT-allo) is currently the only effective treatment of CML. The difficulty of finding a compatible donor and high rates of morbidity and mortality limit transplantation treatment. Despite the safety and efficacy of TKIs, patients can develop resistance. Thus, microRNAs (miRNAs) play a prominent role as biomarkers and post-transcriptional regulators of gene expression. The aim of this study was to analyze the miRNA profile in CML patients who achieved cytogenetic remission after treatment with both HSCT-allo and TKI. Expression analyses of the 758 miRNAs were performed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Bioinformatics tools were used for data analysis. We detected miRNA profiles using their possible target genes and target pathways. MiR-125a-3p stood out among the downregulated miRNAs, showing an interaction network with 52 target genes. MiR-320b was the only upregulated miRNA, with an interaction network of 26 genes. The results are expected to aid future studies of miRNAs, residual leukemic cells, and prognosis in CML.
Publication Date: 2021-10-14
Journal: International journal of molecular sciences

fusion gene(194)

ABL1 and Cofilin1 promote T-cell acute lymphoblastic leukemia cell migration.
The fusion gene of ABL1 is closely related to tumor proliferation, invasion, and migration. It has been reported recently that ABL1 itself is required for T-cell acute lymphoblastic leukemia (T-ALL) cell migration induced by CXCL12. Further experiments revealed that ABL1 inhibitor Nilotinib inhibited leukemia cell migration induced by CXCL12, indicating the possible application of Nilotinib in T-ALL leukemia treatment. However, the interacting proteins of ABL1 and the specific mechanisms of their involvement in this process need further investigation. In the present study, ABL1 interacting proteins were characterized and their roles in the process of leukemia cell migration induced by CXCL12 were investigated. Co-immunoprecipitation in combination with mass spectrometry analysis identified 333 proteins that interact with ABL1, including Cofilin1. Gene ontology analysis revealed that many of them were enriched in the intracellular organelle or cytoplasm, including nucleic acid binding components, transfectors, or co-transfectors. Kyoto Encyclopedia of Genes and Genomes analysis showed that the top three enriched pathways were translation, glycan biosynthesis, and metabolism, together with human diseases. ABL1 and Cofilin1 were in the same complex. Cofilin1 binds the SH3 domain of ABL1 directly; however, ABL1 is not required for the phosphorylation of Cofilin1. Molecular docking analysis shows that ABL1 interacts with Cofilin1 mainly through hydrogen bonds and ionic interaction between amino acid residues. The mobility of leukemic cells was significantly decreased by Cofilin1 siRNA. These results demonstrate that Cofilin1 is a novel ABL1 binding partner. Furthermore, Cofilin1 participates in the migration of leukemia cells induced by CXCL12. These data indicate that ABL1 and Cofilin1 are possible targets for T-ALL treatment.
Publication Date: 2021-09-12
Journal: Acta biochimica et biophysica Sinica

inhibitors tkis(121)

Imatinib co-loaded targeted realgar nanocrystal for synergistic therapy of chronic myeloid leukemia.
Discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML), a malignant myeloproliferative disease characterized by abnormal activation of BCR-ABL fusion oncoprotein with protein tyrosine kinase (PTK) activity. However, the long-term treatment outcomes with TKIs are strongly limited by multiple drug resistances, resulting in relapse albeit with initial high response rate. Here, we reported a realgar (As
Publication Date: 2021-08-25
Journal: Journal of controlled release : official journal of the Controlled Release Society

myeloproliferative neoplasms(105)

Sequential Development of JAK2V617F Mutation and BCR-ABL1 Fusion in Individual Patients With Myeloproliferative Neoplasms: A Linear Clonal Evolution or Parallel Clonal Competition?
Concomitant BCR-ABL1 and JAK2V617F in myeloproliferative neoplasms (MPNs) is rare, and its pathogenesis and clinical significance are unclear. To investigate the clonal relationship between the 2 genomic alterations, as well as the clinicopathologic impact. Retrospective analysis of MPNs with sequential development of BCR-ABL1 and JAK2V617F. Of 6 cases, 5 had JAK2V617F-positive MPN diagnosed before acquiring BCR-ABL1 years later, and 1 had BCR-ABL1+ chronic myeloid leukemia before JAK2V617F-positive myelofibrosis completely replaced the BCR-ABL1+ clone 1 year after tyrosine kinase inhibitor therapy. Among the former group, treatment for the initial MPN involved hydroxyurea, ruxolitinib, and/or supportive care, and the latency to the development of JAK2V617F ranged from 4 to 13 years (median of 9 years). Four cases showed retention of JAK2V617F, whereas BCR-ABL1 emerged as the major clone, including 2 that exhibited parallel increases in JAK2V617F and BCR-ABL1 burdens, with both genomic markers exceeding 50%. Three patients received stem cell transplants and demonstrated sustained engraftment, with the genomic markers below detectable levels. Most MPNs with concomitant JAK2V617F and BCR-ABL1 are actually composite MPNs with a "second hit" residing on a different clone. Rare cases demonstrate a subclone harboring a "double-hit" in a background of a JAK2V617F-positive stem line clone. The probability of a "double-hit" with a BCR-ABL1+ stem line clone is probably reduced by effective tyrosine kinase inhibitor treatment. The treatment often involves combined kinase inhibitors and/or hydroxyurea, but the outcome is unpredictable; hematopoietic stem cell transplantation may be the ultimate therapeutic option for this complicated disease.
Publication Date: 2021-09-11
Journal: Archives of pathology & laboratory medicine

bcr-abl1 transcripts(96)

Aleukemic Extramedullary Blast Crisis as an initial presentation of Chronic Myeloid Leukemia with E1A3 BCR-ABL1 Fusion Transcript.
Right neck swelling and pain occurred in a 49-year-old man. A Blood count showed a slight increase in platelet count without leukemoid reaction. After a biopsy of the cervical mass and bone marrow aspiration, a diagnosis of extramedullary blast crisis (EBC) of chronic myeloid leukemia (CML) was made. FISH analysis showed a BCR-ABL1 fusion signal, but results of RT-PCR for major and minor BCR-ABL1 transcripts were negative. We identified a rare e1a3 BCR-ABL1 fusion transcript. Administration of dasatinib resulted in disappearance of the extramedullary tumor. This is the first reported case of CML-EBC with e1a3 transcript. An aleukemic extramedullary tumor can be the initial presentation of CML.
Publication Date: 2021-09-14
Journal: Internal medicine (Tokyo, Japan)

chronic phase(94)

Atypical activation of signaling downstream of inactivated Bcr-Abl mediates chemoresistance in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) epitomises successful targeted therapy, where inhibition of tyrosine kinase activity of oncoprotein Bcr-Abl1 by imatinib, induces remission in 86% patients in initial chronic phase (CP). However, in acute phase of blast crisis, 80% patients show resistance, 40% among them despite inhibition of Bcr-Abl1 activity. This implies activation of either Bcr-Abl1- independent signalling pathways or restoration of signalling downstream of inactive Bcr-Abl1. In the present study, mass spectrometry and subsequent in silico pathway analysis of differentiators in resistant CML-CP cells identified key differentiators, 14-3-3ε and p38 MAPK, which belong to Bcr-Abl1 pathway. Their levels and activity respectively, indicated active Bcr-Abl1 pathway in CML-BC resistant cells, though Bcr-Abl1 is inhibited by imatinib. Further, contribution of these components to resistance was demonstrated by inhibition of Bcr-Abl1 down-stream signalling by knocking-out of 14-3-3ε and inhibition of p38 MAPK activity. The observations merit clinical validation to explore their translational potential.
Publication Date: 2021-10-02
Journal: Journal of cell communication and signaling

bone marrow(93)

[Investigation of Laboratory and Clinical Feature in the Patients with Myeloproliferative Neoplasm Co-expression of BCR-ABL1 and JAK2 V617F].
To analyze the comprehensive laboratory test data of BCR-ABL1 fusion gene and JAK2 V617F mutation co-expressed in myeloproliferative neoplasm (MPN) patients, and investigate its relative clinical significance. Data of 1 332 MPN patients were comprehensively analyzed, BCR-ABL1 (P190/P210/P230) fusion gene and JAK2 V617F mutation were detected by real time-polymerase chain reaction (RT-PCR) technique, the CALR, MPL, JAK2 12 and 13 exon mutations were detected by the First Generation Sequencing, the bone marrow cell morphology and pathological characteristics were evaluated by bone marrow smear and biopsy technique, the immune phenotypes of bone marrow cells were evaluated by flow cytometry, the chromosome karyotypes of bone marrow cells were analyzed by chromosome G banding technique. Four of the 1 332 patients were found to have the co-existence of BCR-ABL1 fusion gene and the JAK2 V617F mutation, with a 0.3% incidence and a median age of 70 years old, including 2 cases of polycythemia vera, 1 case of primary myelofibrosis, and 1 case of chronic myeloid leukemia-accelerated phase. The clues of double positive genes of such patients at the time of initial diagnose could not be cued only by age, physical signs and cell morphology, they should be analyzed by comprehensive test data. The co-existence of BCR-ABL1 fusion gene and JAK2 V617F mutation in the same case is a kind of disease with special clinical significance. The application of multiple detection methods can improve the detection of this disease, which is conducive to early detection, reasonable diagnosis and treatment by clinicians. 共表达BCR-ABL1与JAK2 V617F的骨髓增殖性肿瘤患者实验室及临床特征分析. 分析BCR-ABL1融合基因和JAK2 V617F突变共表达的骨髓增殖性肿瘤(MPN)患者的实验室检测数据,探讨相关的临床意义. 综合分析1 332例初诊的MPN病例,应用RT-PCR方法检测BCR-ABL1(P190/P210/P230)融合基因及JAK2 V617F基因突变;一代测序方法检测CALR、MPL、JAK2 12和13号外显子突变;骨髓涂片及骨髓活检分析骨髓细胞形态及病理特征;流式细胞术分析骨髓血细胞免疫表型,G显带技术分析骨髓细胞染色体核型. 1 332例患者中4例同时存在BCR-ABL1融合基因和JAK2 V617F突变,发生率为0.3%,患者中位年龄70岁,2例为真性红细胞增多症,1例为原发性骨髓纤维化,1例为慢性髓细胞白血病-加速期。此类患者初诊时单从年龄、体征及细胞形态学上并未提示双阳性基因的线索,需通过综合的检测数据进行分析. BCR-ABL1融合基因和JAK2 V617F突变在同一个患者中共存是一类具有特殊临床意义的疾病,应用多种方法检测可提高此类疾病的检出,有利于临床医生早期发现、合理诊治.
Publication Date: 2021-08-08
Journal: Zhongguo shi yan xue ye xue za zhi

philadelphia chromosome(89)

Leukemia Cell Lines: In Vitro Models for the Study of Chronic Neutrophilic Leukemia.
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm that is genetically characterized by the absence of both the Philadelphia chromosome and BCR-ABL1 fusion gene and the high prevalence of mutations in the colony-stimulating factor 3 receptor (CSF3R). Additional disease-modifying mutations have been recognized in CNL samples, portraying a distinct mutational landscape. Despite the growing knowledge base on genomic aberrations, further progress could be gained from the availability of representative models of CNL. To address this gap, we screened a large panel of available leukemia cell lines, followed by a detailed mutational investigation with focus on the CNL-associated candidate driver genes. The sister cell lines CNLBC-1 and MOLM-20 were derived from a patient with CNL and carry CNL-typical molecular hallmarks, namely mutations in several genes, such as CSF3R, ASXL1, EZH2, NRAS, and SETBP1. The use of these validated and comprehensively characterized models will benefit the understanding of the pathobiology of CNL and help inform therapeutic strategies.
Publication Date: 2021-06-03
Journal: Current oncology (Toronto, Ont.)

international scale(61)

Fluctuation of BCR-ABL1 qPCR
Fluctuation of BCR-ABL1 real-time quantitative polymerase chain reaction in International Scale (qPCR
Publication Date: 2021-05-26
Journal: The Medical journal of Malaysia

stem cells(56)

Future Directions in Chronic Phase CML Treatment.
This review will focus on recent and emerging treatment paradigms in chronic phase CML. The discussion of each novel treatment or drug combination will include a brief overview of scientific rational and pre-clinical data, followed by recently published or ongoing clinical trial efforts. The review will be divided into three focus areas in CML treatment: new frontline approaches and approaches to deepen remission, second treatment-free remission studies, and the treatment of refractory disease. The section on new frontline approaches will highlight several strategies of combination therapy. These can be grouped into immunomodulatory approaches with interferons and immune checkpoint inhibitors, targeting of leukemia stem cells with compounds such as venetoclax and pioglitazone, and BCR-ABL1-intrinsic combination therapy with asciminib. The chance at a second treatment-free remission is an important emerging clinical trial concept, and again combination approaches are under investigation. Lastly, in advanced disease, the development of novel tyrosine kinase inhibitors remains a major focus. This review will provide an overview and perspective of treatment strategies on the horizon for chronic phase CML. Despite the already excellent clinical outcomes for most patients, challenges remain with regard to deepening initial responses, prolonging treatment-free remission, and providing efficacious and tolerable options for patients with refractory disease and resistance mutations.
Publication Date: 2021-10-15
Journal: Current hematologic malignancy reports

leukaemia cml(53)

Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients.
Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785;
Publication Date: 2021-07-02
Journal: British journal of haematology

gene expression(52)

Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma.
Our understanding of the genetics and biology of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia, ALL) has advanced rapidly in the past decade with advances in sequencing and other molecular techniques. Besides recurrent chromosomal abnormalities detected by karyotyping or fluorescence in situ hybridization, these leukemias/lymphomas are characterized by a variety of mutations, gene rearrangements as well as copy number alterations. This is particularly true in the case of Philadelphia-like (Ph-like) ALL, a major subset which has the same gene expression signature as Philadelphia chromosome-positive ALL but lacks BCR-ABL1 translocation. Ph-like ALL is associated with a worse prognosis and hence its detection is critical. However, techniques to detect this entity are complex and are not widely available. This chapter discusses various subsets of ALL and describes our approach to the accurate classification and prognostication of these cases.
Publication Date: 2021-10-10
Journal: Cancer treatment and research

3 months(51)

Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia.
With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximize sustained TFR by improving our understanding of its key determinants. Chronic-phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months of follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.
Publication Date: 2020-09-02
Journal: Blood

bcr-abl1 positive(46)

IL-10 as an Indicator for Predicting Clinical Progression in Acute Lymphoblastic Leukemia Patients.
The aim of this research was to estimate the expression of interleukin-10 in acute lymphoblastic leukemia (ALL) patients before and after chemotherapy in order to evaluate its role as a marker of disease progression. Flow cytometry was used to detect the serum IL-10 levels in ALL patients before and during chemotherapy. Patients were divided into either complete remission (CR) group and non-remission (NR) group, before chemotherapy group and during chemotherapy group, B-ALL group and T-ALL group, WT-1 positive group and BCR-ABL1 positive group. The changes in serum IL-10 concentration before and during the chemotherapy were analyzed. IL-10 serum levels were significantly elevated in ALL patients at the onset of disease, and it was also more elevated in the NR group compared to the CR group. There is a significant reduction in IL-10 serum levels in ALL patients after effective chemotherapy. There was no significant difference between the before chemotherapy group and during chemotherapy group. Regardless of chemotherapy, the IL-10 levels of patients whose bone marrow achieved complete remission were lower than the patients who have not (p < 0.05). The same result can be seen in B or T-ALL groups. There was no significant difference in IL-10 serum levels between the group with WT-1(+) or BCR-ABL1(+) and the group with WT-1(-) or BCR-ABL1(-) (p > 0.05). In some ALL patients, increased IL-10 concentrations may be correlated to the number of peripheral blood leukemic cells. The increase of serum IL-10 level may be a possible marker of disease progression in ALL.
Publication Date: 2021-10-17
Journal: Clinical laboratory

essential thrombocythemia(42)

Novel and combination therapies for polycythemia vera and essential thrombocythemia: the dawn of a new era.
Essential thrombocythemia (ET) and polycythemia vera (PV) belong to the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by the clonal proliferation of hematopoietic stem and progenitor cells. The contribution of aberrant immune regulation within the bone marrow microenvironment to ET and PV pathogenesis as well as the underlying molecular landscape is becoming increasingly understood. Authors searched PubMed and conference abstracts in August 2020 for preclinical and clinical studies to provide an overview of the immune pathobiology in ET and PV and the rationale for several novel agents. A discussion of recent clinical trials on interferon and ruxolitinib in ET and PV patients is provided followed by an outline of the future challenges in the field particularly for novel therapeutics and an increasingly individualized, molecularly driven approach to treatment selection. Several novel agents are currently being actively evaluated and are reviewed herein as well. While hydroxyurea remains the first-line treatment for cytoreduction in most high-risk ET and PV patients, the disease-modifying potential of IFN is promising and could make it a preferred option for selected patients. Advances in molecular testing will enable a more individualized approach to prognostication and treatment selection.
Publication Date: 2020-10-21
Journal: Expert review of hematology

fusion transcripts(42)

Characterization of the immunophenotypic aberrancies with respect to common fusion transcripts in B-cell precursor acute lymphoblastic leukaemia - a report of 986 Indian patients.
Based upon the immunophenotype, acute lymphoblastic leukaemia (ALL) can be categorized into B or T cell lineage (B-cell ALL or T-cell ALL). B-cell precursor ALL (BCP-ALL) cases show various genetic/molecular abnormalities and varying frequencies of chimeric fusion transcripts in BCP-ALL cases are reported from different parts of the world. We studied the immunophenotypic aberrancy profiles of a large number of BCP-ALL cases with respect to various common chimeric fusion transcripts. Flowcytometric Immunophenotyping and Multiplex RT-PCR assay were performed in 986 BCP-ALL cases. Among 986 BCP-ALL cases, the incidence of various fusion transcripts was 38.36% in adult cases and 20.68% in pediatric cases. Adult BCP-ALL cases harbouring t(9;22)(BCR-ABL1) fusion transcripts and having expression of aberrant myeloid markers, were significantly older at presentation (age, p=0.0218) and had male preponderance (male, p=0.0246), as compared to those without aberrant myeloid expression. In pediatric cases expressing t(12;21)(ETV6-RUNX1) chimeric fusion transcript, aberrant expression of CD13 was observed in 39.13%, CD33 in 36.95% and CD117 in 8.69% patients respectively. Pediatric BCP-ALL cases harbouring ETV6-RUNX1 fusion transcript and having expression of aberrant myeloid markers were not significantly different as compared to those without, with respect to their demographic and clinico-hematological characteristics (p=0.5955). Aberrant myeloid markers were rarely/never expressed in pediatric and adult BCP-ALL patients harbouring t(4;11)(KTM2A-AF4) and t(1;19)(TCF3-PBX1) fusion transcripts. Aberrant myeloid markers were frequently expressed among BCP-ALL patients harbouring t(9;22)(BCR-ABL1) and t(12;21)(ETV6-RUNX1) fusion transcripts. However BCP-ALL patients harbouring t(4;11)(KTM2A-AF4) and t(1;19)(TCF3-PBX1) fusion transcripts rarely/ never expressed aberrant myeloid markers. Aberrant myeloid CD markers can be used in predicting chimeric fusion transcripts at baseline, so as to plan desirable TKI therapy in BCP-ALL cases with specific chimeric fusion transcripts. This study delineates the relationship of chimeric fusion transcripts with the aberrant expression of myeloid markers in a large cohort of BCP-ALL cases.
Publication Date: 2021-10-08
Journal: Turkish journal of haematology : official journal of Turkish Society of Haematology

bcr-abl1 negative(42)

Incidence, characteristics and risk factors of thromboembolic events in East Asian patients with BCR-ABL1 negative myeloproliferative neoplasms.
The vascular complications have been a major cause of morbidity and mortality among all subtypes of BCR-ABL1 negative myeloproliferative neoplasms (MPN), but the ethnicity-specific data was limited. We therefore conducted a multi-center retrospective, longitudinal cohort study to evaluate the incidence, characteristics and risk factors of thromboembolic events of MPN patients. Of 256 patients, 27.3% experienced thromboembolic events, majority of which occurred before or within 12 months of MPN diagnosis. The multivariable Cox proportional analyses identified leukocytosis (HR 2.67, 95% CI 1.36-5.24, q = 0.004) and history of thrombosis (HR 9.68, 95% CI 2.00-46.88, q = 0.005) as the risk factors for thromboembolism. In subgroup analysis of polycythemia vera and hemoglobin concentration (HR 1.97, 95% CI 1.28-3.04, q = 0.002) appeared to be a significant risk factor of thrombosis, along with age and thrombosis history. In essential thrombocythemia, severity of the established IPSET score was closely correlated with the frequency of thromboembolic events. In primary myelofibrosis, history of thrombosis was associated with thrombosis events (HR 13.85, 95% CI 1.2-159.5, q = 0.035). Overall survival was worse in patients who experienced thromboembolic events. Our study highlighted the importance of recognizing high risk patients and implementing personalized intervention.
Publication Date: 2021-09-10
Journal: Scientific reports

hybridization fish(31)

Chronic myeloid leukemia-leukemia cutis mimicking a neutrophilic panniculitis-like leukemia cutis: Report of a rare case.
While drug-induced panniculitis is not uncommon in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor therapy, it is rare for CML to initially present as a leukemic panniculitis. We present the case of a 45-year-old male with no relevant prior medical history presenting with 6 months of migratory nodules, 2 months of drenching night sweats, and a 20 pound weight loss. Physical examination showed firm subcutaneous nodules with overlying ecchymoses present on the right lateral thigh and left lower back. Biopsy of a nodule from the right thigh showed a subcutaneous lobular panniculitis involved by a dense infiltrate of neutrophils and granulocyte precursors. Fluorescent in-situ hybridization (FISH) was positive for t(9;22)(q34;q11.2)BCR-ABL1 fusion. A concurrent hemogram revealed a white blood cell count elevation of 600,000 K/μL. Bone marrow biopsy examination showed marked myeloid expansion with an increase in granulocyte precursors and Philadelphia chromosome positivity by FISH, consistent with bone marrow involvement by CML. Herein, we describe this unusual and rare case of CML initially presenting as a neutrophilic panniculitis-like leukemia cutis. Arriving at this challenging diagnosis may be easily missed without clinical and laboratory correlation, which would certainly lead to the patient's not receiving life-saving treatment.
Publication Date: 2021-04-24
Journal: Journal of cutaneous pathology

imatinib mesylate(31)

Alterations in Sialylation Patterns are Significantly Associated with Imatinib Mesylate Resistance in Chronic Myeloid Leukemia.
The study examined sialylation changes for their potential predictive value in assessment of imatinib mesylate (IM) resistance, alone and/or with BCR-ABL1 transcript variants among chronic myeloid leukemia (CML) cases. A total of 98 CML cases (un-treated cases, IM non-responders and IM responders) were enrolled in the study. Total sialic acid (TSA) and total protein (TP) levels were estimated spectrophotometrically, the expression profiles of BCR-ABL1, ST3GAL1 and ST3GAL2 were evaluated using qRT-PCR assays and BCR-ABL1 transcript variants were identified through subjecting PCR products to agarose gel electrophoresis. The results manifested increase in e14a2 transcript and decrease in co-expression of both transcripts (e13a2 and e14a2) in IM non-responders than un-treated CML cases. Notably, TSA/TP ratio was higher, whereas ST3GAL1 and ST3GAL2 expressions were lower in un-treated CML cases and IM non-responders as against IM responders. Further, ST3GAL2 expression was lower in un-treated CML cases than IM non-responders. Receiver operating characteristic curves also proved their discriminatory efficiencies. Decisively, the rise in TSA levels and the fall in ST3GAL1 and ST3GAL2 levels were evidently related to CML progression and clinical indicators of treatment failure (high BCR-ABL1 ratio, high WBC count, high platelet count and low Hb levels). The alterations in TSA, ST3GAL1 and ST3GAL2 levels were remarkably associated with each other. The altered levels of TSA, ST3GAL1 and ST3GAL2 are, to a significant extent, associated with IM resistance in CML, which have clinical relevance in treatment monitoring and IM resistance treatment.
Publication Date: 2021-07-20
Journal: Archives of medical research

cml patients(29)

Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib.
Adverse vascular events have become a serious clinical problem in chronic myeloid leukemia (CML) patients who receive certain BCR/ABL1 tyrosine kinase inhibitors (TKIs). Studies have shown that endothelial-to-mesenchymal transition (EndMT) can contribute to various vascular diseases. We investigated the effects of TKIs on the development of EndMT in human vascular-endothelial cells (VECs). Exposure of VECs to dasatinib, but not to other TKIs, produced a significant increase in the formation of spindle-shaped cells. This effect was accompanied by a significant increase in expression of the EndMT inducer transforming growth factor-β (TGF-β) and mesenchymal markers vimentin, smooth muscle alpha-actin, and fibronectin, as well as a significant decrease in expression of vascular-endothelial markers CD31 and VE-cadherin attributable at least in part to activation of ERK signaling. Inhibitors of TGF-β and ERK partially attenuated dasatinib-induced EndMT. Interestingly, bosutinib efficiently counteracted dasatinib-induced EndMT and attenuated dasatinib-induced phosphorylation of ERK. Taken together, these results show that dasatinib induces EndMT, which might contribute to the development of vascular toxicity, such as the pulmonary hypertension observed in CML patients receiving dasatinib. Bosutinib could play a distinct role in protecting VECs from EndMT.
Publication Date: 2021-01-05
Journal: International journal of hematology

neoplasms mpns(29)

Clinical and Molecular Attributes of Patients With BCR/ABL1-negative Myeloproliferative Neoplasms in India: Real-world Data and Challenges.
Classic BCR/ABL1-negative myeloproliferative neoplasms (MPNs) are characterized by clinical and genetic heterogeneity and include 4 distinct constituents. Very little data on clinical presentation and epidemiology of the same is available from the Indian setting. Patients referred to Hematology-Oncology from January 2018 to August 2020 with suspected MPNs were included in the analysis and prospectively followed-up. All patients were initially screened, and only those meeting the updated World Health Organization 2016 criteria were included in the analysis. Epidemiologic, clinical, and molecular characteristics were documented, and patients were followed-up prospectively. A total of 233 patients were referred for evaluation of MPN, of which 63 were included in the analysis, including 39 males and 24 females. The median age at diagnosis was 57 years (range, 28-82 years), and 38% patients were younger than 50 years of age. The most common presentations were incidental detection in 35 (55.5%), abdominal symptoms in 13 (20%), fatiguability in 7 (11%), and recent vascular events in 6 (9.5%) patients. Final diagnosis was polycythemia vera in 27, essential thrombocytosis (ET) in 21, prefibrotic myelofibrosis in 9, and myelofibrosis in 6 patients. The frequency of driver mutations in polycythemia vera included JAK2 in 75%; in ET, JAK2 in 33%, CALR in 33%, and MPL in 4%; and in prefibrotic myelofibrosis, JAK2 in 66% and CALR in 33%. Aspirin was used for all patients along with risk-adapted cytoreduction with hydroxyurea. Ruxolitinib was reserved for symptoms refractory to hydroxyurea. After a median follow-up of 15 months (interquartile range, 10-28 months) from diagnosis, disease progression was noted in 4 patients. Two patients died at the end of the follow-up period, including 1 with secondary acute myeloid leukemia post myelofibrosis and one with ET and coexistent oral malignancy. The remaining 61 patients are alive and on regular treatment. This is one of the first systematic descriptions and prospective follow-up of patients with BCR/ABL-negative MPNs from India. Our study indicates a younger median age of presentation and higher proportion of JAK2-unmutated disease across all subtypes. The primary role of bone marrow morphology and supportive role of somatic mutations in differentiating MPN subtypes is indicated. This study sets the stage for a collaborative registry for defining epidemiologic data and long-term outcomes with MPN in India.
Publication Date: 2021-03-25
Journal: Clinical lymphoma, myeloma & leukemia

vera pv(26)

Conformation sensitive gel electrophoresis for the detection of calreticulin mutations in BCR-ABL1-negative myeloproliferative neoplasms.
Calreticulin (CALR) mutations in myeloproliferative neoplasms (MPN) have been reported to be key markers in the molecular diagnosis, particularly in patients lacking JAK2 V617F mutation. In most current reports, CALR mutations were analysed by either allele-specific PCR (AS-PCR), or the more expensive quantitative real-time PCR, pyrosequencing and next-generation sequencing. Hence, we report the use of an alternative method, the conformation sensitive gel electrophoresis (CSGE) for the detection of CALR mutations in BCR-ABL1-negative MPN patients. Forty BCR-ABL1-negative MPN patients' DNA: 19 polycythemia vera (PV), 7 essential thrombocytosis (ET) and 14 primary myelofibrosis (PMF), were screened for CALR mutations by CSGE. PCR primers were designed to amplify sequences spanning between exons 8 and 9 to target the mutation hotspots in CALR. Amplicons displaying abnormal CSGE profiles by electrophoresis were directly sequenced, and results were analysed by BioEdit Sequence Alignment Editor v7.2.6. CSGE results were compared with AS-PCR and confirmed by Sanger sequencing. CSGE identified 4 types of mutations; 2 PMF patients with either CALR type 1 (c.1099_1150del52) or type 2 (c.1155_1156insTTGTC), 1 ET patient with nucleotide deletion (c.1121delA) and insertion (c.1190insA) and 1 PV patient with p.K368del (c.1102_1104delAAG) and insertion (c.1135insA) inframe mutations. Three patients have an altered KDEL motif at the C-terminal of CALR protein. In comparison, AS-PCR only able to detect two PMF patients with mutations, either type 1 and type 2. CSGE is inexpensive, sensitive and reliable alternative method for the detection of CALR mutations in BCR-ABL1-negative MPN patients.
Publication Date: 2021-06-15
Journal: International journal of laboratory hematology

jak2 v617f(25)

Ascites in a young male: idiopathic FIP1L1-PDGFRA-negative hypereosinophilic syndrome.
Idiopathic hypereosinophilic syndrome is defined as persistently elevated peripheral blood absolute eosinophil count of more than 1.5 × 109/L for at least six months with no obvious secondary cause. We report the case of a 26-year-old gentleman of Malay ethnicity who presented to the medical department with a three-week history of abdominal distension associated with dyspepsia and epigastric pain. Physical examination revealed ascites. The complete blood count portrayed peripheral leucocytosis with eosinophilia of 8.84 × 109/L. Parasitic serology was negative. Paracentesis analysis showed exudative ascites with an absolute eosinophil count of 8 × 109/L. He was referred to the haematology department. He was noticed to have bilateral tonsillitis and pruritic skin rash at the legs. There were no palpable lymph nodes or organomegaly. A peripheral blood film showed 44% eosinophils with no excess blasts. Clonal eosinophilic fusion studies did not detect FIP1L1-PDGFRA mutation. JAK2 V617F and BCR-ABL1 mutations were undetected. Serum B12 and tryptase levels were normal. A whole-body computed tomography imaging showed bowel wall thickening at the duodenum, jejunum, ileum, rectosigmoid and splenic flexure. Sections of fragments taken from the endoscopy showed features of eosinophilic gastritis and colitis on histology. Bone marrow biopsy depicted marked eosinophilia. He was started on oral imatinib mesylate 200 mg daily and oral prednisolone 0.5 mg/kg daily which was tapered based on response. He achieved complete remission and is now asymptomatic. The diagnosis of hypereosinophilic syndrome should be considered in a patient with unexplained ascites. Secondary sinister causes such as malignancy should always be excluded.
Publication Date: 2020-02-01
Journal: JRSM open

95 ci(12)

Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation.
To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).
Publication Date: 2021-03-09
Journal: Blood

22 bcr-abl1(10)

Clinical and genomic characterization of patients diagnosed with the provisional entity acute myeloid leukemia with BCR-ABL1, a Swedish population-based study.
Acute myeloid leukemia (AML) with t(9;22)(q34;q11), also known as AML with BCR-ABL1, is a rare, provisional entity in the WHO 2016 classification and is considered a high-risk disease according to the European LeukemiaNet 2017 risk stratification. We here present a retrospective, population-based study of this disease entity from the Swedish Acute Leukemia Registry. By strict clinical inclusion criteria we aimed to identify genetic markers further distinguishing AML with t(9;22) as a separate entity. Twenty-five patients were identified and next-generation sequencing using a 54-gene panel was performed in 21 cases. Interestingly, no mutations were found in NPM1, FLT3, or DNMT3A, three frequently mutated genes in AML. Instead, RUNX1 was the most commonly mutated gene, with aberrations present in 38% of the cases compared to around 10% in de novo AML. Additional mutations were identified in genes involved in RNA splicing (SRSF2, SF3B1) and chromatin regulation (ASXL1, STAG2, BCOR, BCORL1). Less frequently, mutations were found in IDH2, NRAS, TET2, and TP53. The mutational landscape exhibited a similar pattern as recently described in patients with chronic myeloid leukemia (CML) in myeloid blast crisis (BC). Despite the concomitant presence of BCR-ABL1 and RUNX1 mutations in our cohort, both features of high-risk AML, the RUNX1-mutated cases showed a superior overall survival compared to RUNX1 wildtype cases. Our results suggest that the molecular characteristics of AML with t(9;22)/BCR-ABL1 and CML in myeloid BC are similar and do not support a distinction of the two disease entities based on their underlying molecular alterations.
Publication Date: 2021-01-13
Journal: Genes, chromosomes & cancer

n 2(3)

Clinicopathological characteristics of de novo and secondary myeloid sarcoma: A monocentric retrospective study.
Diagnosing myeloid sarcoma remains challenging, and we aimed to provide clinicopathological features to facilitate diagnosis. Clinicopathological data from 41 patients with de novo and 31 with secondary myeloid sarcoma were reviewed. Most de novo cases presented with isolated myeloid sarcoma (n = 19) or myeloid sarcoma with concurrent acute myeloid leukemia (n = 15). Most secondary cases presented after acute myeloid leukemia (n = 11), myeloproliferative neoplasm (n = 9), or myelodysplastic syndrome (n = 8). Most frequent localizations were skin and lymph nodes. Immunohistochemistry showed immature and/or aberrant antigenic expression in 29% of de novo and 39% of secondary cases. Most genetic abnormalities were RUNX1-RUNX1T1 (n = 4), CBFB-MYH11 (n = 2), KMT2A-MLLT3 (n = 2), and JAK2 V617F (n = 2) mutations in de novo myeloid sarcoma, and BCR-ABL1 (n = 5) and KMT2A rearrangements (n = 2) in secondary cases. A complex karyotype was seen in 17% of de novo and 39% of secondary cases. Most prevalent treatment was induction chemotherapy followed by consolidation chemotherapy (n = 10) or allogeneic stem cell transplantation (n = 9) for de novo and radiotherapy (n = 11) for secondary cases. De novo myeloid sarcoma mostly presented isolated. Lesions were often localized at skin and lymph nodes. Genetic aberrations frequently involved core-binding factor rearrangements in de novo cases and a complex karyotype in secondary cases.
Publication Date: 2018-03-14
Journal: European journal of haematology


Treatment-Free Remission: the New Goal in CML Therapy.
Treatment-free remission (TFR) is considered one of the main goals of therapy in patients with CML. Our goal in this paper is to review the current data on TFR, and discuss future directions. Multiple studies have demonstrated that attempting a treatment-free remission is safe and effective in a select group of patients. More recent data suggested that undetectable BCR-ABL1 by digital PCR prior to discontinuation is highly predictive of successful TFR. However, some patients have a successful TFR with no evidence of clinical disease despite persistent detectable BCR-ABL1. Some recent studies have shed some more light on possible mechanisms for this phenomena. Some possible mechanisms include immune mechanism, BCR-ABL1 detected in the lymphoid component only, or stem cell exhaustion. TFR should be discussed with patients with CML. Patients who achieve a sustained deep molecular response may be eligible to attempt TFR, however, setting expectations that overall only 20% of patients with newly diagnosed CML will achieve a successful TFR. The importance of compliance to treatment early on cannot be overemphasized. Further studies using other drugs to get patients to a deeper remission in order to be eligible for TFR attempt, or attempting a second TFR in patients who had disease recurrence after first TFR attempt, are currently underway.
Publication Date: 2021-10-08
Journal: Current hematologic malignancy reports


Pathological and genomic phenotype of second neuroendocrine carcinoma during long-term follow-up after radical radiotherapy for nasopharyngeal carcinoma.
Second head and neck neuroendocrine carcinoma (NEC) after radical radiotherapy for nasopharyngeal carcinoma (NPC) treatment is rarely reported. The prognosis of second cancer is poor, and our research focuses on finding a breakthrough in the treatment. In this study, we aimed to investigate clinicopathological characteristics and to identify the genomic landscape of second head and neck NECs. We collected five second head and neck NEC cases in the recent three years from our patient database. Clinicopathological data and images were obtained. Genomic analysis was performed using high-throughput second generation sequencing. KEGG pathway enrichment analyses between high-frequency mutations were performed using the STRING database. All patients had been diagnosed with second NEC, according to the pathological observations. The interval between diagnosis of NPC and NEC ranged from 10 to 18 years. Two patients had brain or liver metastasis at three and nine months, respectively, after the diagnosis of NEC. Three patients died of the disease with the overall survival time ranging from three to nine months. Commonly altered genes (50%) in second head and neck NECs included TP53, RB1, NOTCH2, PTEN, POLG, KMT2C, U2AF1, EPPK1, ELAC2, DAXX, COL22A1, and ABL1. Those genetic lesions might affect p53 signaling, MAPK signaling, PI3K-Akt signaling, sphingolipid signaling, and neurotrophin signaling pathways. Second head and neck NECs had poor prognosis. We revealed, for the first time, the mutational landscape, high-frequency somatic mutations, and potential signaling pathways of second head and neck NECs. Its optimal treatment model needs to be further studied in future clinical trials.
Publication Date: 2021-10-13
Journal: Radiation oncology (London, England)


New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m
Publication Date: 2021-09-26
Journal: Cell death & disease


Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells.
Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the survival of chronic myeloid leukemia (CML) patients, but measurable residual disease typically persists. To more effectively eradicate leukemia cells, simultaneous targeting of BCR-ABL1 and additional CML-related survival proteins has been proposed. Notably, several highly specific myeloid cell leukemia 1 (MCL1) inhibitors have recently entered clinical trials for various hematologic malignancies, although not for CML, reflecting the insensitivity of CML cell lines to single MCL1 inhibition. Here, we show that combining TKI (imatinib, nilotinib, dasatinib, or asciminib) treatment with the small-molecule MCL1 inhibitor S63845 exerted strong synergistic antiviability and proapoptotic effects on CML lines and CD34+ stem/progenitor cells isolated from untreated CML patients in chronic phase. Using wild-type BCR-ABL1-harboring CML lines and their T315I-mutated sublines (generated by CRISPR/Cas9-mediated homologous recombination), we prove that the synergistic proapoptotic effect of the drug combination depended on TKI-mediated BCR-ABL1 inhibition, but not on TKI-related off-target mechanisms. Moreover, we demonstrate that colony formation of CML but not normal hematopoietic stem/progenitor cells became markedly reduced upon combination treatment compared to imatinib monotherapy. Our results suggest that dual targeting of MCL1 and BCR-ABL1 activity may efficiently eradicate residual CML cells without affecting normal hematopoietic stem/progenitors.
Publication Date: 2021-09-27
Journal: Cell death & disease


Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition.
The ribonucleotide reductase inhibitor hydroxyurea suppresses de novo dNTP synthesis and attenuates the hyperproliferation of leukemic blasts. Mechanisms that determine whether cells undergo apoptosis in response to hydroxyurea are ill-defined. We used unbiased proteomics to uncover which pathways control the transition of the hydroxyurea-induced replication stress into an apoptotic program in chronic and acute myeloid leukemia cells. We noted a decrease in the serine/threonine kinase RAF1/c-RAF in cells that undergo apoptosis in response to clinically relevant doses of hydroxyurea. Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea. We further disclose that pharmacological inhibition of the RAF downstream target BCL-XL with the drug navitoclax and RNAi combine favorably with hydroxyurea against leukemic cells. BCR-ABL1 and hyperactive FLT3 are tyrosine kinases that causally contribute to the development of leukemia and induce RAF1 and BCL-XL. Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations.
Publication Date: 2021-07-25
Journal: Cancers


Overview of clinical and genetic features of CML patients with variant Philadelphia translocations involving chromosome 7: A case series.
Variant Philadelphia (Ph) translocations involving chromosome 7 are rarely seen in Chronic Myeloid Leukemia (CML) patients. It is aimed to contribute new cases to the literature by reviewing the cases in our archive and shed light into the understanding of the role of chromosome 7 in CML. This study was carried out in 237 newly diagnosed CML patients with variant Ph translocations. Among the patients, those with variant Ph translocation involving chromosome 7 were evaluated in terms of clinical and genetic characteristics. Chromosome analysis was performed on 24 and 48 h of bone marrow cultures. FISH analysis was performed with BCR-ABL1 dual color dual fusion translocation probes. BCR-ABL1 transcript levels were analysed by QRT-PCR and results were reported as BCR-ABL1/ABL1 (BCR-ABL1 (IS) %) according to international scale. Four of the patients had variant Ph translocations including chromosome 7. The karyotypes were 46,XX,t(7;9;22)(p13;q34;q11); 46,XX,t(7;9;22)(p21;q34;q11); 46,XX,t(7;9;22)(q22;q34;q11) and 46,XY,t(7;9;22)(q22;q34;q11). The breakpoints demonstrated by cytogenetic analysis were confirmed by FISH analysis. Monitoring by QRT-PCR showed that patients with variant Ph translocation including 7p13 and 7p21 had a dramatic decrease in BCR-ABL1 levels resulting in complete hematological, complete cytogenetic and deep molecular responses. Despite achieving complete hematological, complete cytogenetic response in two patients with variant Philadelphia translocation, including 7q22, no major molecular response was achieved and both patients are still in the warning category. Response to tyrosine kinase inhibitör therapy may be associated with both the variant translocation mechanism and new gene interactions that occur due to the breakpoints of additional chromosomes involved in translocation.
Publication Date: 2021-10-12
Journal: Leukemia research


Pharmacokinetics of Asciminib in Individuals With Hepatic or Renal Impairment.
Asciminib is an investigational, first-in-class, specifically targeting the ABL myristoyl pocket (STAMP) inhibitor of BCR-ABL1 with a new mechanism of action compared with approved ATP-competitive tyrosine kinase inhibitors. This report describes the findings from 2 phase 1 studies assessing the pharmacokinetic (PK) profile of a single dose of asciminib (40 mg) in individuals with impaired renal function (based on absolute glomerular filtration rate; NCT03605277) or impaired hepatic function (based on Child-Pugh classification; NCT02857868). Individuals with severe renal impairment exhibited 49%-56% higher exposure (area under the curve [AUC]), with similar maximum plasma concentration (C
Publication Date: 2021-06-12
Journal: Journal of clinical pharmacology


IKZF1 alterations are not associated with outcome in 498 adults with B-precursor ALL enrolled in the UKALL14 trial.
IKZF1 deletions (ΔIKZF1) are commonly detected in B-precursor acute lymphoblastic leukemia (ALL; B-ALL) and are widely assumed to have a significant impact on outcome. We compared the ability of multiplex ligand-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) to detect ΔIKZF1 and to determine the impact on event-free survival of patients with precursor B-ALL aged 23 to 65 years recruited to the completed trial UKALL14 (ISRCTN 66541317). From 655 recruits with BCR-ABL1+ and BCR-ABL1- B-ALL, all available diagnostic DNA samples (76% of the recruited population) were screened by multiplex end point PCR covering 4 deletions: dominant-negative (DN) Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 (n = 498), MLPA (n = 436), or by both (n = 420). Although patients with BCR-ABL1- ΔIKZF1 were more likely to have minimal residual disease at the end of induction, we did not find any impact of ΔIKZF1 (including subgroup analysis for DN or loss-of-function lesions) or the IKZF1plus genotype on event-free, overall survival, or relapse risk by univariable or multivariable analyses. Consistent with the technical approach, MLPA not only detected a wider range of deletions than PCR but also failed to detect some PCR-detected lesions. The main difference between our study and others reporting an association between ΔIKZF1 and outcome is the older age of participants in our population. The impact of ΔIKZF1 in ALL may be less marked in an older population of patients. Our study underscores the need for analyses in large, harmonized data sets. This trial was registered at as #NCT01085617.
Publication Date: 2021-09-04
Journal: Blood advances


Quantitative analysis of IKZF1 gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia: higher levels are associated with a poorer prognosis.
To assess the prognostic effect of different levels of IKZF1 gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). IKZF1 Δ2-8/ALB deletions were quantified using multiplex real-time quantitative PCR in newly diagnosed pediatric BCP-ALL patients. Seventy-four patients with IKZF1 deletions ≥ 0.01% were included. Clinical characteristics, laboratory data, and treatment outcomes were analyzed. The patients were divided into two groups: IKZF1 deletions <1% (group A) and ≥1% (group B). Group B patients had a higher BCR-ABL1 positive rate than group A patients. The proportions of patients who had an age at onset ≥10 years old, and white blood cell count ≥50 × 10
Publication Date: 2021-09-29
Journal: Pediatric hematology and oncology


Inference of kinase-signaling networks in human myeloid cell line models by Phosphoproteomics using kinase activity enrichment analysis (KAEA).
Despite the introduction of targeted therapies, most patients with myeloid malignancies will not be cured and progress. Genomics is useful to elucidate the mutational landscape but remains limited in the prediction of therapeutic outcome and identification of targets for resistance. Dysregulation of phosphorylation-based signaling pathways is a hallmark of cancer, and therefore, kinase-inhibitors are playing an increasingly important role as targeted treatments. Untargeted phosphoproteomics analysis pipelines have been published but show limitations in inferring kinase-activities and identifying potential biomarkers of response and resistance. We developed a phosphoproteomics workflow based on titanium dioxide phosphopeptide enrichment with subsequent analysis by liquid chromatography tandem mass spectrometry (LC-MS). We applied a novel Kinase-Activity Enrichment Analysis (KAEA) pipeline on differential phosphoproteomics profiles, which is based on the recently published SetRank enrichment algorithm  with reduced false positive rates. Kinase activities were inferred by this algorithm using an extensive reference database comprising five experimentally validated kinase-substrate meta-databases complemented with the NetworKIN in-silico prediction tool. For the proof of concept, we used human myeloid cell lines (K562, NB4, THP1, OCI-AML3, MOLM13 and MV4-11) with known oncogenic drivers and exposed them to clinically established kinase-inhibitors. Biologically meaningful over- and under-active kinases were identified by KAEA in the unperturbed human myeloid cell lines (K562, NB4, THP1, OCI-AML3 and MOLM13). To increase the inhibition signal of the driving oncogenic kinases, we exposed the K562 (BCR-ABL1) and MOLM13/MV4-11 (FLT3-ITD) cell lines to either Nilotinib or Midostaurin kinase inhibitors, respectively. We observed correct detection of expected direct (ABL, KIT, SRC) and indirect (MAPK) targets of Nilotinib in K562 as well as indirect (PRKC, MAPK, AKT, RPS6K) targets of Midostaurin in MOLM13/MV4-11, respectively. Moreover, our pipeline was able to characterize unexplored kinase-activities within the corresponding signaling networks. We developed and validated a novel KAEA pipeline for the analysis of differential phosphoproteomics MS profiling data. We provide translational researchers with an improved instrument to characterize the biological behavior of kinases in response or resistance to targeted treatment. Further investigations are warranted to determine the utility of KAEA to characterize mechanisms of disease progression and treatment failure using primary patient samples.
Publication Date: 2021-07-10
Journal: BMC cancer


Comparison of Two Quantitative PCR-Based Assays for Detection of Minimal Residual Disease in B-Precursor Acute Lymphoblastic Leukemia Harboring Three Major Fusion Transcripts.
Two quantitative PCR (qPCR)-based methods, for clonal immunoglobulin or T-cell receptor gene (Ig/TCR) rearrangements and for fusion transcripts, are widely used for the measurement of minimal residual disease (MRD) in patients with B-precursor acute lymphoblastic leukemia (ALL). MRD of bone marrow samples from 165 patients carrying the three major fusion transcripts, including 74 BCR-ABL1, 54 ETV6-RUNX1, and 37 TCF3-PBX1, was analyzed by using the two qPCR-based methods. The correlation coefficient of both methods was good for TCF3-PBX1 (R
Publication Date: 2021-07-30
Journal: The Journal of molecular diagnostics : JMD


Gupta V, Kim S, Hu Z-H, et al. Comparison of outcomes of HCT in blast phase of BCR-ABL1- MPN with de novo AML and with AML following MDS. Blood Adv. 2020;4(19):4748-4757.
Publication Date: 2021-06-05
Journal: Blood advances


Role of the ABL tyrosine kinases in the epithelial-mesenchymal transition and the metastatic cascade.
The ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease. Video abstract.
Publication Date: 2021-05-24
Journal: Cell communication and signaling : CCS