pubmed > ABL1 > neoplasms mpns

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

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

Successful Treatment of a Patient with Chronic Myelogenous Leukemia with Concurrent Janus Kinase 2 (JAK2) R795S Mutation and Breakpoint Cluster Region-ABL1 (BCR-ABL1) Fusion: A Case Report and Literature Review.
BACKGROUND Although the V617F mutation in the Janus kinase 2 (JAK2) gene and the breakpoint cluster region-abl1 (BCR-ABL1) oncogene fusion have been considered mutually exclusive in most myeloproliferative neoplasms (MPNs), many recent studies have described patients with both. This report describes a patient with chronic myelogenous leukemia (CML) and the unusual JAK2 R795S mutation and reviews 23 additional patients with JAK2 gene mutations coexisting with myelofibrosis (MF) and CML. CASE REPORT A 50-year-old woman with MF experienced rapid disease progression 3 weeks later, accompanied by severe abdominal pain and a white blood cell count of 257.45×10⁹/l. Karyotype analysis indicated that she was 46, XY, Philadelphia (Ph) (+) and BCR-ABL1 positive. Bone marrow aspiration after 1 cycle of chemotherapy and treatment with dasatinib showed that her marrow was hypercellular, with an increased number of megakaryocytes and 48.5% myeloblasts expressing the myeloid antigens CD33, CD13, CD34, CD117, and CD71. Next-generation sequencing identified a rare JAK2 R795S mutation. She was diagnosed with CML in blast phase, and was successfully treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). CONCLUSIONS JAK2 gene mutations, including the rare JAK2 R795S mutation, can coexist with BCR-ABL1 in patients with MPNs. The clinical course of MPN in patients with both BCR-ABL1 and JAK2 mutations may be different from that in patients with classical MPNs.
Publication Date: 2020-10-07
Journal: The American journal of case reports

Comparison of outcomes of HCT in blast phase of BCR-ABL1- MPN with de novo AML and with AML following MDS.
Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.
Publication Date: 2020-10-03
Journal: Blood advances

Risk of disease transformation and second primary solid tumors in patients with myeloproliferative neoplasms.
This study aimed to elucidate patterns of disease transformation to secondary myelofibrosis (SMF) or secondary acute myeloid leukemia (SAML) and the development of second primary malignancies in South Korean patients with BCR-ABL1-negative myeloproliferative neoplasms (MPNs). By using nationwide public health care insurance claims data, we identified and analyzed 7454 patients with MPNs who were newly diagnosed with essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF) from 2008 to 2016 and used the data to appropriately trace the disease course. Transformation to SMF or SAML was rare in patients with ET and PV, but patients with PMF had an 8-year cumulative incidence of SAML of 21.4%. Patients with PV or ET had an 8-year cumulative incidence of second primary solid tumors of ∼14%. Patients with MPNs had a 2 times higher risk of developing second primary solid tumors than that of the general South Korean population. Compared with patients with PMF, patients with SMF had a similar overall survival with a lower risk of developing SAML. The use of ruxolitinib did not increase the risk of developing B-cell lymphoma over a median follow-up period of 16.2 months. Disease transformation to SMF or SAML was rare in patients with ET or PV, but SAML was common in patients with PMF. South Korean patients with MPNs had a significantly higher risk of developing second primary solid tumors than that of the general population, particularly for kidney, prostate, brain, liver, and lung cancers.
Publication Date: 2019-11-26
Journal: Blood advances

Clinical and molecular profile of a Brazilian cohort of patients with classical BCR-ABL1-negative myeloproliferative neoplasms.
The classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). In developing countries, there are few reports that truly reveal the clinical setting of these patients. Therefore, we aimed to characterize a single center MPN population with a special focus on the correct diagnosis based on the recent review of the WHO criteria for the diagnosis of myeloid neoplasms. This retrospective study analyzed data from medical records of patients with classical BCR-ABL1-negative MPNs diagnosed from January 1997 to October 2017 and followed at the University Hospital of Ribeirão Preto Medical School. A total of 162 patients were assessed, 61 with PV, 50 with ET, and 51 with PMF. The mutational status analysis revealed that 113 (69.3%) harbored the JAK2V617F mutation, 23 (14.1%), the CALR mutation, and 12 (7.4%) had a triple-negative status. None of the patients were found to have mutations on the thrombopoietin receptor gene (MPL), including some ET and PMF patients who were not tested. Among the PV patients, 57 (93.5%) were positive for the JAK2V617F mutation, one (1.6%) presented an in-frame deletion JAK2 exon 12 mutation and one (1.6%) presented a missense JAK2 exon 9 mutation, not previously described. The overall survival was lower in the triple-negative patients with PMF, when compared to the JAK2V617F or CALR-mutated (p = 0.002). The frequency of somatic mutations and survival in our cohort, stratified according to the respective disease, was consistent with the literature data, despite some limitations. Further prospective epidemiological studies of MPN cohorts are encouraged in developing countries.
Publication Date: 2019-11-05
Journal: Hematology, transfusion and cell therapy

Management of advanced phase myeloproliferative neoplasms.
The BCR-ABL1-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, can evolve into a form of secondary acute myeloid leukemia termed MPN in blast phase (MPN-BP). MPN in accelerated phase (MPN-AP), which is defined by 10% to 19% myeloid blasts in the peripheral blood or bone marrow, is a precursor to MPN-BP. Alternative definitions of MPN-AP exist based on studies identifying clinical variables that portend a poor prognosis and high risk for progression to MPN-BP. Allogeneic hematopoietic stem cell transplant remains the only curative therapeutic option; however, advanced age and high comorbidity index preclude the majority of patients from receiving this treatment modality. This article reviews management considerations for the advanced-phase MPNs (MPN-AP and MPN-BP), with a special focus on MPN-AP, and highlights novel experimental therapies.
Publication Date: 2019-08-27
Journal: Clinical advances in hematology & oncology : H&O

Endothelial Cells Harbouring the JAK2V617F Mutation Display Pro-Adherent and Pro-Thrombotic Features.
Thromboembolic events are the main cause of mortality in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) but their underlying mechanisms are largely unrecognized. The Janus kinase 2 (JAK2)
Publication Date: 2018-08-14
Journal: Thrombosis and haemostasis

GATA1 Expression in BCR/ABL1-negative Myeloproliferative Neoplasms.
This study aimed to determine GATA1 expression levels to better characterize subgroups in BCR/ABL1-negative myeloproliferative neoplasms (MPNs). This study enrolled 49 patients diagnosed as having BCR/ABL1-negative MPN on the basis of the 2016 World Health Organization classification : nine polycythemia vera (PV), 17 essential thrombocythemia (ET), 12 prefibrotic primary myelofibrosis (prePMF), and 11 overt primary myelofibrosis (PMF). Relevant clinical and laboratory data were retrieved from the medical records. The molecular analysis of CALR and MPL mutations and quantification of JAK2 V617F allele burden were performed. GATA1 expression was assessed by an immunohistochemical assay on bone marrow biopsy. GATA1 expression was analyzed serially in 18 patients. GATA1 expression decreased significantly in PMF compared with that in other subtypes, while no statistical difference was identified between ET and prePMF. GATA1 expression did not differ according to the mutation profiles or the allele burden of JAK2 V617F, but it decreased significantly in patients with overt fibrosis or leukemic transformation. Our results suggest that GATA1 expression is significantly low in PMF and decreases with progressive fibrosis and possibly with leukemic transformation, although our attempt to accurately distinguish between subgroups using GATA1 immunohistochemical approach did not achieve statistical significance. A large patient cohort with long term follow-up is required to evaluate the prognostic value of GATA1 expression.
Publication Date: 2018-04-04
Journal: Annals of laboratory medicine

Angiogenesis in JAK2 V617F positive myeloproliferative neoplasms and ruxolitinib decrease VEGF, HIF-1 enesis in JAK2 V617F positive cells.
Angiogenesis and JAK2 V617F mutation are common in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). Ruxolitinib, a JAK inhibitor, is an effective treatment for some MPNs. However, the relationship between angiogenesis and JAK2 V617F and the effects of ruxolitinib on angiogenesis are still unknown. Here, we observed the correlation of JAK2 V617F mutation burden with VEGF, HIF-1a and microvascular density (MVD) in MPNs. We investigate the effect of ruxolitinib on the expression of VEGF and HIF-1α in JAK2 V617F positive cells. We found the expression levels of p-JAK2, VEGF, HIF-1a and MVD in the newly diagnosed MPNs were significantly increased and were related to the JAK2 V617F burden. Ruxolitinib can inhibit p-JAK2, VEGF, HIF-1a expression and suppress blood vessels' formation in chick embryo choriallantoic membrane. Our findings indicated that angiogenesis is related to JAK2 V617F burden and ruxolitinib could decrease VEGF and HIF-1a expression in JAK2 V617F positive cells.
Publication Date: 2017-05-31
Journal: Leukemia & lymphoma

Multicenter analysis of the use of transjugular intrahepatic portosystemic shunt for management of MPN-associated portal hypertension.
BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are clonal stem cell disorders defined by proliferation of one or more myeloid lineages, and carry an increased risk of vascular events and progression to myelofibrosis and leukemia. Portal hypertension (pHTN) occurs in 7-18% of MPN patients via both thrombotic and nonthrombotic mechanisms and portends a poor prognosis. Transjugular intrahepatic portosystemic shunt (TIPS) has been used in the management of MPN-associated pHTN; however, data on long-term outcomes of TIPS in this setting is limited and the optimal management of medically refractory MPN-associated pHTN is not known. In order to assess the efficacy and long-term outcomes of TIPS in MPN-associated pHTN, we performed a retrospective analysis of 29 MPN patients who underwent TIPS at three academic medical centers between 1997 and 2016. The majority of patients experienced complete clinical resolution of pHTN and its clinical sequelae following TIPS. One, two, three, and four-year overall survival post-TIPS was 96.4%, 92.3%, 84.6%, and 71.4%, respectively. However, despite therapeutic anticoagulation, in-stent thrombosis occurred in 31.0% of patients after TIPS, necessitating additional interventions. In conclusion, TIPS can be an effective intervention for MPN-associated pHTN regardless of etiology. However, TIPS thrombosis is a frequent complication in the MPN population and indefinite anticoagulation post-TIPS should be considered.
Publication Date: 2017-05-26
Journal: American journal of hematology

Clinical and hematological relevance of JAK2 V617F and CALR mutations in BCR-ABL-negative ET patients.
Classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis frequently harbor JAK2, MPL, and CALR somatic mutations. AS-PCR for JAK2 V617F, pyrosequencing for MPL W515L/K, and PCR-fragment analysis for CALR exon 9 mutations were established to analyze genomic DNA isolated from peripheral blood samples of 58 newly diagnosed ET patients in Thailand. JAK2 V617F was detected in 41 patients (71%) and CALR exon 9 mutation was positive in eight patients (14%), whereas no mutation of MPL W515L/K was observed in this study. Patients with CALR mutation were older (p = 0.023) and exhibited lower number of platelet count (p = 0.041) than patients without CALR mutation. Two previously known CALR mutation types were identified in this study (six patients with CALR-type 1 and two patients with CALR-type 2). Additionally, no co-existence of JAK2 V617F and CALR mutations was identified in this work. We reported the frequency of JAK2 V617F, MPL W515L/K, and CALR mutations in Thai patients with ET. Clinical and hematological phenotypes of patients were associated with JAK2 and CALR mutation statuses. The combination of laboratory testing for the detection of JAK2, CALR, and MPL mutations is necessary to improve the diagnosis and classification of BCR-ABL1-negative MPN.
Publication Date: 2017-04-14
Journal: Hematology (Amsterdam, Netherlands)

Chronic kidney disease in the BCR-ABL1-negative myeloproliferative neoplasm: a single-center retrospective study.
Renal complications related to BCR-ABL1-negative myeloproliferative neoplasms (MPNs) have not been examined fully in Asian populations. We analyzed estimated glomerular filtration rate (eGFR) and its changes with time retrospectively in patients with BCR-ABL1-negative MPN from 2005 to 2015. The prevalence of chronic kidney disease (CKD) was 11% (6.6% having stage 3 and 4.4% having stage 4). In a linear regression analysis of eGFR versus time (years), overall, patients showed increased eGFR (mL/min/1.73 m2) by 0.51 (95% confidence interval [CI], -0.30 to 1.33; p = 0.22). Patients with polycythemia vera (PV), and those treated with hydroxyurea, showed statistically significant increases in eGFR (1.59; 95% CI, 0.28 to 2.90; p = 0.02 in PV; and 1.55; 95% CI, 0.56 to 2.54; p = 0.02 in treatment with hydroxyurea). In total, 17 patients (20.5%) showed rapid loss of eGFR (< -3 mL/min/1.73 m2 per year). This rapid loss in eGFR was associated with a higher incidence of kidney disease (23.5% vs. 6.1%, p = 0.05) and a higher percentage of patients with high neutrophil (> 7.0 × 109 /L) and high monocyte (> 0.7 × 109 /L) counts (76.5% vs. 50%, p = 0.05; 52.9% vs. 28.8%, p = 0.06, respectively). More patients had high serum lactate dehydrogenase (> 500 U/L) levels (52.9% vs. 25.8%, p = 0.03) at diagnosis. CKD is prevalent in patients with BCR-ABL1-negative MPN. Active cytoreductive therapy has the potential to improve kidney function in BCR-ABL1-negative MPN.
Publication Date: 2017-03-17
Journal: The Korean journal of internal medicine

Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations.
Increased angiogenesis in BCR-ABL1 negative myeloproliferative neoplasms (MPNs) has been recognized, but its connection with clinical and molecular markers needs to be defined. The aims of study were to (1) assess bone marrow (BM) angiogenesis measured by microvessel density (MVD) using CD34 and CD105 antibodies; (2) analyze correlation of MVD with plasma angiogenic factors including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8; (3) examine the association of MVD with clinicopathological and molecular markers. We examined 90 de novo MPN patients (30 polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET)) and 10 age-matched controls. MVD was analyzed by immunohistochemistry "hot spot" method, angiogenic factors by immunoassay and JAK2V617F, and CALR mutations by DNA sequencing and allelic PCR. MVD was significantly increased in MPNs compared to controls (PMF > PV > ET). Correlation between MVD and plasma angiogenic factors was found in MPNs. MVD was significantly increased in patients with JAK2V617F mutation and correlated with JAK2 mutant allele burden (CD34-MVD: ρ = 0.491, p < 0.001; CD105-MVD: ρ = 0.276, p = 0.02) but not with CALR mutation. MVD correlated with leukocyte count, serum lactate dehydrogenase, hepatomegaly, and splenomegaly. BM fibrosis was significantly associated with CD34-MVD, CD105-MVD, interleukin-8, and JAK2 mutant allele burden. JAK2 homozygote status had positive predictive value (100%) for BM fibrosis. Patients with prefibrotic PMF had significantly higher MVD than patients with ET, and we could recommend MVD to be additional histopathological marker to distinguish these two entities. This study also highlights the strong correlation of MVD with plasma angiogenic factors, JAK2 mutant allele burden, and BM fibrosis in MPNs.
Publication Date: 2016-12-08
Journal: Annals of hematology

pSTAT3/pSTAT5 Signaling Patterns in Molecularly Defined Subsets of Myeloproliferative Neoplasms.
BCR/ABL1-negative myeloproliferative neoplasms (MPNs) are characterized by recurrent mutations in JAK2, CALR, and MPL, each of which has been reported to alter JAK/STAT signaling pathways. This report characterizes JAK/STAT signaling patterns in molecularly defined subsets of MPN utilizing immunohistochemistry for pSTAT3 and pSTAT5. Analysis of 30 BCR/ABL1-negative, nonpolycythemia vera MPN identified 15 (50%) with JAK2 V617F, 2 with MPL mutations (7%), and 8 with CALR mutations (27%). All mutations were mutually exclusive, except for 1 case with concurrent JAK2 V617F and CALR mutations. pSTAT3 staining in megakaryocyte nuclei was found in 4 cases (13%) and was not significantly associated with mutation status. pSTAT5 staining in megakaryocyte nuclei was found in 16 cases (53%), as was significantly associated with JAK2 V617F versus CALR mutation (P=0.009). Erythroid staining for pSTAT5 was seen exclusively in "triple-negative (TN)" cases lacking JAK2 V617F, MPL, and CALR mutations (P=0.006, TN vs. other genotypes), and pSTAT5 staining in megakaryocyte nuclei was seen in 2 TN cases. pSTAT5 staining in TN MPN suggests that other unknown abnormalities in this pathway may contribute to the pathogenesis of these cases. Furthermore, the demonstration of distinct STAT staining patterns in molecularly defined MPN suggests that these mutations result in divergent signaling events that may contribute to the biological and prognostic differences in these molecular subsets of MPN.
Publication Date: 2016-06-04
Journal: Applied immunohistochemistry & molecular morphology : AIMM

Detection of mutations in JAK2 exons 12-15 by Sanger sequencing.
The Janus kinase (JAK)2 p.V617F gain-of-function mutation is a hallmark of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). This study analyzed JAK2 mutations in 1811 patients tested between 2010 and 2013. Exons 12-15 of JAK2 were sequenced in 1706 samples, and patients harboring mutations were clinically evaluated. Of 271 patients (16%) with JAK2 mutations, 148 (54.6%) were female and 123 (45.4%) were male; 103 (38%) were local and 168 (62%) were referred; and 13 (5%) had additional genetic abnormalities. The median patient age was 54 years, and there was only one pediatric patient. In agreement with previous reports, 262 patients (96.7%) were positive for the JAK2 p.V617F mutation. Non-p.V617F JAK2 mutations were detected in the remaining nine (3.3%) patients: five (1.8%) had a p.G571S mutation, and one (0.3%) each had p.E543_D544del, p.Y570Y silent, p.R541_E543delinsK, and p.I540_N542delinsM mutations. Diagnosis of 103 (38%) in-house cases revealed a predominance of MPN patients (87 cases, or 84.4%). JAK2 p.V617F was the most prevalent mutation detected among patients in this study. Non-p.V617F JAK2 mutations were identified in exons 12 and 13 corresponding to recently reported mutations, except for the novel p.I540_N542delinsM.
Publication Date: 2015-09-12
Journal: International journal of laboratory hematology

The Prevalence of JAK2, MPL, and CALR Mutations in Chinese Patients With BCR-ABL1-Negative Myeloproliferative Neoplasms.
To evaluate the mutation frequency of JAK2 V617F, JAK2 exon 12, MPL exon 10, and CALR exon 9 and the value of the combined tests in the diagnosis of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). In the current study, mutations of JAK2 V617F, JAK2 exon 12, MPL exon 10, and CALR exon 9 were analyzed in 929 Chinese patients with BCR-ABL1-negative MPN, including 234 cases of polycythemia vera (PV), 428 ETs, 187 PMFs, and 80 unclassifiable MPNs (MPN-Us). Our result showed that the positive rate of any of four mutations in patients with PV, ET, PMF, and MPN-U was 89.3%, 83.4%, 87.2%, and 77.5%, respectively, which significantly improved the diagnostic rate, especially in ET and PMF. Meanwhile, we also found that the patients without any of four mutations were younger than those with one or more mutations. Unexpectedly, the coexistence of JAK2 V617F and CALR exon 9 was identified in six (0.6%) patients, and JAK2 V617F and MPL exon 10 were present simultaneously in two (0.2%) patients. In addition, we also identified several novel mutation types in CALR exon 9. The combined genetic tests of JAK2 V617F, JAK2 exon 12, MPL exon 10, and CALR exon 9 help improve the diagnostic rate for BCR-ABL1-negative MPN.
Publication Date: 2015-06-14
Journal: American journal of clinical pathology

Transformation of an Unclassified Myeloproliferative Neoplasm with a Rare BCR-JAK2 Fusion Transcript Resulting from the Translocation (9;22)(p24;q11).
BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1  negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.
Publication Date: 2015-03-20
Journal: Case reports in hematology

Is there a role for JAK inhibitors in BCR-ABL1-negative myeloproliferative neoplasms other than myelofibrosis?
Current data suggest that constitutively active JAK-STAT signaling plays a central role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasms (MPNs), regardless of the specific underlying molecular abnormality. This observation provides strong rationale for use of JAK inhibitors for MPN treatment, and these drugs were first tested in myelofibrosis (MF) patients. Ruxolitinib, a JAK-1/2 inhibitor, is effective at controlling splenomegaly and constitutional symptoms, but has limited benefit in reversing bone marrow fibrosis or inducing complete or partial remissions. Ruxolitinib is currently in Phase 3 testing for treatment of hydroxyurea resistant/intolerant polycythemia vera (PV). Preliminary data reveals response rates of 60% for hematocrit control and 38% for spleen volume reduction per protocol-defined criteria, in addition to improving disease-related symptoms. These endpoints however have limited value as surrogates for long-term clinically relevant outcomes such as freedom-from-cardiovascular/thrombohemorrhagic events or time-to-hematological transformation, and the early crossover design of the aforementioned trial introduces limitations in terms of analysis of these latter endpoints. In contrast, other recent trials in PV have demonstrated the feasibility of using long-term clinically relevant outcomes as a primary endpoint. We also discuss the role of JAK inhibitors for treatment of CSF3RT618I-mutated chronic neutrophilic leukemia and hematologic malignancies with rearranged JAK2 gene.
Publication Date: 2014-12-19
Journal: Leukemia & lymphoma

Novel insights into the biology and treatment of chronic myeloproliferative neoplasms.
Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoiesis characterized by a high frequency of genetic alterations, and include chronic myeloid leukemia (CML) and the BCR-ABL1-negative MPNs. Herein we summarize recent advances and controversies in our understanding of the biology and therapy of these disorders, as discussed at the 8th post-American Society of Hematology CML-MPN workshop. The principal areas addressed include the breakthrough discovery of CALR mutations in patients with JAK2/MPL wild type MPN, candidate therapies based on novel genetic findings in leukemic transformation and new therapeutic targets in MPNs, and an appraisal of bone marrow histopathology in MPNs with a focus on the potential new clinical entity of "masked" polycythemia vera. An update on clinical trials of Janus kinase (JAK) inhibitors is presented as well as current understanding regarding the definitions and mechanisms of resistance to JAK inhibitors, and updated information on the safety and efficacy of discontinuation of tyrosine kinase inhibitors in patients with CML.
Publication Date: 2014-10-21
Journal: Leukemia & lymphoma