Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders

AbstractAn acquired gain-of-function mutation in the Janus kinase 2 (JAK2-V617F) is frequently found in patients with myeloproliferative disorders (MPDs). To test the hypothesis that JAK2-V617F is the disease-initiating mutation, we examined whether all cells of clonal origin carry the JAK2-V617F mutation. Using allele-specific polymerase chain reaction (PCR) assays for the JAK2 mutation and for the X-chromosomal clonality markers IDS and MPP1, we found that the percentage of granulocytes and platelets with JAK2-V617F was often markedly lower than the percentage of clonal granulocytes determined by IDS or MPP1 clonality assays in female patients. Using deletions of chromosome 20q (del20q) as an autosomal, X-chromosome–independent clonality marker, we found a similar discrepancy between the percentage of cells carrying JAK2-V617F and del20q. Our results suggest that in a proportion of patients with MPDs, JAK2-V617F occurs on the background of clonal hematopoiesis caused by a somatic mutation in an as-yet-unknown gene.

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Myeloid Blasts in Transformed JAK2-V617F Positive Myeloproliferative Disorders Are Frequently Negative for the JAK2-V617F Mutation.

Blood ◽

10.1182/blood.v108.11.375.375 ◽

2006 ◽

Vol 108 (11) ◽

pp. 375-375 ◽

Cited By ~ 4

Author(s):

Alexandre Theocharides ◽

Marjorie Boissinot ◽

Richard Garand ◽

François Girodon ◽

Soon-Siong Teo ◽

...

Keyword(s):

De Novo ◽

Jak2 V617f ◽

Myeloproliferative Disorders ◽

Jak2 V617f Mutation ◽

Jak2 Mutation ◽

Allelic Ratio ◽

Pcr Products ◽

Blast Cells ◽

V617f Mutation ◽

De Novo Aml

Abstract Acute myeloid leukemia (AML) is a common complication of myeloproliferative disorders (MPDs). The role of the JAK2-V617F mutation in this process is unknown. We performed a retrospective analysis of DNA samples from MPD patients with secondary AML. We analysed DNA samples taken at the time of transformation to AML from 54 MPD patients (24 PV, 21 ET, 9 IMF). In addition, DNA samples taken at diagnosis of MPD were obtained in 21 of these patients. DNA was extracted from bone marrow or peripheral blood films, purified granulocytes or frozen cells. FACS sorting of blast cells, T cells and neutrophils was performed in some of the samples. The allelic ratio of JAK2-V617F was determined by allele-specific quantitative PCR (AS-PCR). We obtained AS-PCR data on 52/54 samples taken at the time of transformation (96%), whereas 2 samples did not yield PCR products: 24/52 samples were negative for JAK2-V617F (46%) and 28/52 were positive (54%). For 14/24 negative patients (58%) we had additional DNA samples taken at the time of MPD diagnosis and interestingly, 5 of these 14 patients (36%) were positive for JAK2-V617F at this earlier time point before AML transformation. This suggests that in these patients the JAK2-V617F positive clone was lost during the evolution to AML. Furthermore, comparison of the JAK2-V617F allelic ratios with the percentage of blast cells in patient samples positive at transformation revealed 8/28 cases where the JAK2-V617F allelic ratio was markedly lower than the percentage of blasts, e.g. 8%T-allele and 52% myeloid blast cells. In these patients a JAK2-V617F negative AML clone most likely co-exists with a JAK2-V617F positive MPD clone. To address the question whether the AML clone arose independently from the JAK2-V617F clone, we analyzed loss of heterozygosity on chromosome 9p (9pLOH) in one informative patient who displayed a high allelic ratio of mutant JAK2 at diagnosis (94%T). The CD15+ cells from this patient showed 9pLOH at diagnosis, as demonstrated with two independent microsatellite markers. In contrast, the FACS sorted blast cells at the time of transformation contained both parental alleles in the 9p region and were JAK2-V617F negative by AS-PCR. This excludes the possibility that the AML clone lost the JAK2V617F in the process of undergoing mitotic recombination at a stage heterozygous for JAK2-V617F. Analysis of additional patients is under way. In summary, we found in a cohort of 54 MPD patients, 13 patients initially positive for JAK2-V617F that transformed into JAK2-V617F negative AML. Although not confirmed in the one patient analyzed, we cannot exclude that other patients the JAK2-V617F positive MPD clone lost the JAK2 mutation during the process of transformation. Alternatively, the AML clone could have developed de novo from a JAK2-V617F negative progenitor or stem cell. The latter model has difficulties explaining the high incidence of de novo AML (8/54 patients), unless the JAK2-V617F negative progenitor already carried an as yet unknown mutation and was part of the MPD clone.

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Correlation of JAK2 V617F Mutation Status and Cytogenetic Findings in Myeloproliferative Disorders.

Blood ◽

10.1182/blood.v108.11.3633.3633 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3633-3633

Author(s):

Guoxian Sun ◽

Frank Buccini ◽

Elizabeth Fuentes ◽

James Weisberger

Keyword(s):

Jak2 V617f ◽

Myeloproliferative Disorders ◽

Chromosome Abnormalities ◽

Jak2 V617f Mutation ◽

Homozygous Mutation ◽

Jak2 Mutation ◽

Mutation Status ◽

Trisomy 9 ◽

V617f Mutation ◽

Trisomy 9P

Abstract Detection of JAK2 V617F mutation is quickly becoming a front-line screening test for suspected myeloproliferative disorders (MPDs), as the mutation shows high frequency and specificity in non-CML MPDs, PV, ET or CIMF. Routine cytogenetics can detect chromosome abnormalities in approximately 20% of MPDs and is very helpful in establishing or confirming the presence of aberrant clonality, although chromosome changes are often numerical gains and losses, deemed non-specific. To see if there is correlation between JAK2 mutation and karyotypes, we studied 57 consecutive patients with clinically and morphologically confirmed diagnosis of non-CML MPDs. JAK2 V617F mutation performed using allele-specific PCR (sensitive to 10% using pyrosequencing) was found in 72% of patients (41/57), whereas clonal chromosome abnormalities were observed in 15.8% (9/57). There was no correlation between JAK2 mutational status and karyotypes. In 41 patients positive for the JAK2 mutation, 6 were cytogenetically abnormal and 35 normal. In 16 patients negative for the mutation, 3 showed abnormal karyotypes and 13 had normal karyotypes (X2 test, p>0.5). Among 6 patients with both JAK2 mutation and an abnormal karyotype, JAK2 mutation was seen in >50% of each sample in 4 patients, consistent with a homozygous mutation. Interestingly, in two cases, one with PV and trisomy 9 and another with MPD unclassifiable and trisomy 9p resulting from an unbalanced translocation between chromosomes 9p and 13, JAK2 mutation was present in >65% of each sample. Trisomy 9 and trisomy 9p are common abnormalities in MPDs, particularly in PV, seen in over 20% of cytogenetically abnormal cases. JAK2 gene is located on 9p24. Mitotic recombination is considered the most likely cause of loss of heterozygosity (LOH) and thus mutant homozygosity which is undetectable at the cytogenetic level. However, in cases with trisomy 9 or 9p, the JAK2 allele genotypes may be G/T/T and/or T/T/T as well as the usual G/T and/or T/T. Our observations suggest that trisomy 9 or 9p should be taken into consideration when interpreting JAK2 mutation status and that further molecular studies are needed to delineate the implication of trisomy 9 or 9p in potential mutant allele selective advantage and clonal evolution in JAK2 mutation positive MPDs.

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Detection of the JAK2 V617F Mutation by Real Time PCR in Granulocytes and Platelets of ET Patients.

Blood ◽

10.1182/blood.v108.11.4877.4877 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4877-4877

Author(s):

Beatriz Bellosillo ◽

Eva Gimeno ◽

Raquel Longaron ◽

Lourdes Florensa ◽

Antonio Salar ◽

...

Keyword(s):

Real Time ◽

Direct Sequencing ◽

Specific Treatment ◽

Jak2 V617f ◽

Jak2 V617f Mutation ◽

Wild Type ◽

Rt Pcr ◽

Jak2 Mutation ◽

Allele Specific ◽

V617f Mutation

Abstract Introduction. The JAK2 V617F mutation has been detected in 23%–57% of ET patients by direct sequencing or allele-specific (AS) PCR. It remains unknown, however, if the mutation detected in the granulocyte population, may be equally detected in platelets from these patients. Objective. To compare the detection of the JAK2V617F mutation in granulocytes and platelets from ET patients by real time AS RT-PCR. Patients and methods. Platelets and granulocytes from 50 ET patients from a single institution were studied. Patients were diagnosed according to the WHO criteria. At the time when JAK2 mutation was analyzed 16/50 patients were receiving platelet-lowering therapy ± ASA, 14/50 patients only received ASA and 20/50 received no specific treatment. JAK2 mutation was analyzed by real-time AS RT-PCR with probes specific for the mutated and the wild type form. Results. The V617F JAK2 mutation was detected in 18 out of 50 patients in both granulocytes and platelets by real time AS RT-PCR, and was negative in both cell populations in the remaining 32 patients. In the V617F JAK2 positive cases, the mean Ct(V617FJAK2)/Ct(wild type JAK2) ratio was 1.074±0.062 for granulocytes and 1.038±0.039 for platelets (p=0.048). These values corresponded to a 17.79 ±7.4% of mutated population when granulocytes were analyzed, whereas, a significantly higher percentage of mutated population was observed, 23.45±7.78 %, when platelets were analyzed (p=0.032). Conclusions. The results of V617FJAK2 mutation detection by AS RT-PCR were the same in granulocytes and platelets (either positive or negative). The percentage of clonal population detected in ET patients was significantly higher in platelets than in granulocytes.

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Leukemic blasts in transformed JAK2-V617F–positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation.

Blood ◽

10.1182/blood-2006-12-062125 ◽

2007 ◽

Vol 110 (1) ◽

pp. 375-379 ◽

Cited By ~ 222

Author(s):

Alexandre Theocharides ◽

Marjorie Boissinot ◽

François Girodon ◽

Richard Garand ◽

Soon-Siong Teo ◽

...

Keyword(s):

Myeloid Leukemia ◽

Jak2 V617f ◽

Myeloproliferative Disorders ◽

Microsatellite Analysis ◽

Jak2 V617f Mutation ◽

Leukemic Transformation ◽

Clonal Origin ◽

V617f Mutation ◽

Acute Myeloid

To study the role of the JAK2-V617F mutation in leukemic transformation, we examined 27 patients with myeloproliferative disorders (MPDs) who transformed to acute myeloid leukemia (AML). At MPD diagnosis, JAK2-V617F was detectable in 17 of 27 patients. Surprisingly, only 5 of 17 patients developed JAK2-V617F–positive AML, whereas 9 of 17 patients transformed to JAK2-V617F–negative AML. Microsatellite analysis in a female patient showed that mitotic recombination was not responsible for the transition from JAK2-V617F–positive MPD to JAK2-V617F–negative AML, and clonality determined by the MPP1 polymorphism demonstrated that the granulocytes and leukemic blasts inactivated the same parental X chromosome. In a second patient positive for JAK2-V617F at transformation, but with JAK2-V617F–negative leukemic blasts, we found del(11q) in all cells examined, suggesting a common clonal origin of MPD and AML. We conclude that JAK2-V617F–positive MPD frequently yields JAK2-V617F–negative AML, and transformation of a common JAK2-V617F–negative ancestor represents a possible mechanism.

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Somatic mutation of the V617F JAK2 gene in patients of the cardiovascular diseases

Terapevticheskii arkhiv ◽

10.26442/00403660.2019.07.000245 ◽

2019 ◽

Vol 91 (7) ◽

pp. 25-28

Author(s):

I A Olkhovskiy ◽

A S Gorbenko ◽

M A Stolyar ◽

D A Grischenko ◽

O A Tkachenko ◽

...

Keyword(s):

Somatic Mutation ◽

Venous Blood ◽

Jak2 V617f ◽

Jak2 V617f Mutation ◽

Vascular Pathology ◽

Thrombotic Risk ◽

Cardiovascular Patients ◽

Allele Specific ◽

Polymerase Chain ◽

V617f Mutation

The JAK2 V617F somatic mutation is one of the most frequent markers of CHIP (clonal hematopoiesis of indeterminate potential). CHIP is characterized by the presence of a myeloid cells clone in peripheral blood in the absence of the sufficient reasons to diagnose the hematologic disease. The CHIP is proposed as a potential independent risk factor for vascular pathology. The aim of this study is to identify carriers of JAK2 V617F mutation among patients admitted for planned hospitalization at the Federal Center of Cardiovascular Surgery of Krasnoyarsk. Materials and methods. The study included 930 venous blood samples. JAK2 V617F mutation was detected by using the allele - specific real time polymerase chain reaction. Results. JAK2 V617F mutation was detected in 15 (1.6%) patients, but only two of them had blood cell count that could cause a hematological disease to be suspected. Conclusion. The inclusion of the JAK2 V617F mutation detection in the complex of laboratory tests of the cardiovascular patients can facilitate the timely identification of patients with increased thrombotic risk, as well as the timely diagnosis of myeloproliferative diseases.

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Coexistence of a Heterozygous JAK2(V617F) Mutation and a Secondary BCR-ABL Translocation within the Compartment of Committed Myeloid Progenitors in Chronic Idiopathic Myelofibrosis.

Blood ◽

10.1182/blood.v108.11.4871.4871 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4871-4871

Author(s):

Martin Bornhaeuser ◽

Brigitte Mohr ◽

Uta Oelschlaegel ◽

Peter Bornhauser ◽

Swen Jacki ◽

...

Keyword(s):

Bone Marrow ◽

Philadelphia Chromosome ◽

Jak2 V617f ◽

Janus Kinase ◽

Jak2 V617f Mutation ◽

Idiopathic Myelofibrosis ◽

Jak2 Mutation ◽

V617f Mutation ◽

Chronic Idiopathic Myelofibrosis ◽

Philadelphia Chromosome Positive

Abstract Myeloproliferative disorders such as polycythemia vera (PV), essential thrombocytosis (ET) and chronic idiopathic myelofibrosis (CIMF) are clonal hematopoietic diseases with clinical similarities including the risk of transformation into acute myelogeneous leukemia. By definition, these diseases have been separated from Philadelphia chromosome positive (Ph+) CML requiring negativity for the BCR-ABL transcript in PCR studies of bone marrow or peripheral blood. Several groups independently discovered a gain of function mutation of the Janus kinase 2 (JAK2) gene in Ph-negative myeloproliferative diseases. This mutation has been associated with the proliferation of clonogenic progenitors independently of exogenous cytokine stimulation. A sixty-six year old male patient presented with moderate splenomegaly (3 cm under the costal marigin), mild anemia (11.3 g/dl), elevated lactate deyhdrogenase, an increased count of circulating CD34+ cells and a dry bone marrow aspirate. Marrow histology confirmed a prefibrotic stage of chronic idiopathic myelofibrosis (CIMF). Metaphase cytogenetics as well as BCR-ABL FISH were performed on samples from bone marrow, blood and sorted CD34+, CD3+, CD19+ and CD14+ cells from a steady-state back-up leukapheresis. The JAK2(V617F) mutation was confirmed by an allele-specific PCR assay. A screen for BCR-ABL was performed by FISH and PCR in sorted cells as well as in individual colonies (CFU-GM and CFU-E). Four Philadelphia-chromosome positive metaphases could be detected out of 86 derived from the autologous leukapheresis product harvested and cryopreserved as back-up shortly after diagnosis. The BCR-ABL translocation could be detected by fluorescence in-situ hybridisation (FISH) in 2/16 (12.5%) isolated granulocyte/macrophage colonies only whereas all erythroid colonies were negative. The JAK2 mutation was detectable in all clones and was enriched in CD34+ selected cells. The patient experienced progressive splenomegaly despite the achievement of a molecular response measured by quantitative BCR-ABL PCR after treatment with imatinib mesylate. Our in-vitro investigations suggest that the secondary BCR-ABL translocation within the myeloid compartment was of minor pathophysiological relevance in this patient with CIMF harbouring a heterozygous JAK2 mutation.

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Should We Screen for Janus Kinase 2 V617F Mutation in Cerebral Venous Thrombosis?

Cerebrovascular Diseases ◽

10.1159/000471891 ◽

2017 ◽

Vol 44 (3-4) ◽

pp. 97-104 ◽

Cited By ~ 5

Author(s):

Matthias Lamy ◽

Paola Palazzo ◽

Pierre Agius ◽

Jean Claude Chomel ◽

Jonathan Ciron ◽

...

Keyword(s):

Venous Thrombosis ◽

Cerebral Venous Thrombosis ◽

Myeloproliferative Neoplasms ◽

Jak2 V617f ◽

Janus Kinase ◽

Jak2 V617f Mutation ◽

Janus Kinase 2 ◽

Jak2 Mutation ◽

Venous Thromboembolic Events ◽

V617f Mutation

Background: The presence of Janus Kinase 2 (JAK2) V617F mutation represents a major diagnostic criterion for detecting myeloproliferative neoplasms (MPN) and even in the absence of overt MPN, JAK2 V617F mutation is associated with splanchnic vein thrombosis. However, the actual prevalence and diagnostic value of the JAK2 V617F mutation in patients with cerebral venous thrombosis (CVT) are not known. The aims of this study were to assess the prevalence of JAK2 V617F mutation in a large group of consecutive CVT patients, to detect clinical, biological, and radiological features associated with the mutation, and to determine the long-term venous thrombosis recurrence rate in CVT patients with JAK2 mutation but without overt MPN in order to recommend the best preventive treatment. Methods: This was a prospective study conducted on consecutive patients with a first-ever radiologically confirmed CVT. JAK2 V617F mutation analysis was assessed in all the study subjects. JAK2 V617F-positive patients were followed up to detect new venous thrombotic events. Results: Of the 125 included subjects, 7 were found to have JAK2 V617F mutation (5.6%; 95% CI 2.3-11.2). Older age (p = 0.039) and higher platelet count (p = 0.004) were independently associated with JAK2 V617F positivity in patients without overt MPN. During a mean follow-up period of 59 (SD 46) months, 2 JAK2 V617F-positive patients presented with 4 new venous thromboembolic events. Conclusions: Screening for the JAK2 V617F mutation in CVT patients seems to be useful even in the absence of overt MPN and/or in the presence of other risk factors for CVT because of its relatively high prevalence and the risk of thrombosis recurrence.

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JAK2-V617F mutation in patients with myeloproliferative neoplasms: Association with FLT3-ITD mutation

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1010614s ◽

2010 ◽

Vol 138 (9-10) ◽

pp. 614-618

Author(s):

Vesna Spasovski ◽

Natasa Tosic ◽

Tatjana Kostic ◽

Sonja Pavlovic ◽

Milica Colovic

Keyword(s):

Cell Proliferation ◽

Myeloproliferative Neoplasms ◽

Myeloid Cell ◽

Jak2 V617f ◽

Signalling Pathway ◽

Janus Kinase ◽

Jak2 V617f Mutation ◽

Polycythaemia Vera ◽

Jak2 Mutation ◽

V617f Mutation

Introduction. An acquired somatic mutation V617F in Janus kinase 2 gene (JAK2) is the cause of uncontrolled proliferation in patients with myeloproliferative neoplasms. It is known that uncontrolled myeloid cell proliferation is also provoked by alteration in other genes, e.g. mutations in receptor tyrosine kinase FLT3 gene. FLT3 represents the most frequently mutated gene in acute myeloid leukaemia. Interestingly, mutated FLT3- ITD (internal tandem duplication) protein is a member of the same signalling pathway as JAK2 protein, the STAT5 signalling pathway. STAT5 activation is recognized as important for selfrenewal of haematopoetic stem cells. Objective. The aim of this study was the detection of JAK2- V617F mutation in patients with myeloproliferative neoplasms. Additionally, we investigated the presence of FLT3-ITD mutation in JAK2-V617F-positive patients in order to shed the light on the hypothesis of a similar role of these two molecular markers in haematological malignancies. Methods. Using allele-specific PCR, 61 patients with known or suspected diagnosis of myeloproliferative neoplasms were tested for the presence of JAK2-V617F mutation. Samples that were positive for JAK2 mutation were subsequently tested for the presence of FLT3-ITD mutation by PCR. Results. Eighteen of 61 analysed patients were positive for JAK2-V617F mutation. Among them, 8/18 samples were diagnosed as polycythaemia vera, and 10/18 as essential thrombocythaemia. None of JAK2-V617F-positive patient was positive for FLT3-ITD mutation. Conclusion. This study suggests that one activating mutation is sufficient for aberrant cell proliferation leading to malignant transformation of haematopoetic stem cell.

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JAK2 V617F Mutation in Essential Thrombocythemia.

Blood ◽

10.1182/blood.v108.11.4925.4925 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4925-4925

Author(s):

Jeong Yeal Ahn ◽

Pil Whan Park ◽

Yiel Hea Seo ◽

Dong-Bok Shin ◽

Jae-Hoon Lee ◽

...

Keyword(s):

Bone Marrow ◽

Essential Thrombocythemia ◽

Statistical Significance ◽

Vascular Complications ◽

Jak2 V617f ◽

Myeloproliferative Disorders ◽

Janus Kinase ◽

Jak2 Mutation ◽

Hematopoietic Stem ◽

Specific Association

Abstract Background: Essential thrombocythemia (ET) is thought to reflect transformation of a multipotent hematopoietic stem cell, but its molecular pathogenesis has remained obscure. But tyrosine kinase, especially Janus kinase 2 (JAK2) has been implicated in myeloproliferative disorders other than chronic myeloid leukemia. We investigated the incidence and its correlation with other clinicopathologic variables of JAK2 mutation in patients with ET and reactive thrombocytosis (RT). Method: JAK2 mutation analysis, using allele-specific polymerase chain reaction, was undertaken on genomic DNA from bone marrow aspirates of 24 patients with ET and peripheral blood in 36 patients with RT. Results: JAK2 mutation was detected in 11 patients (46%) among the 24 patients with ET and was not found in 36 patients with RT. In patients with ET, older age and leukocytosis were related with JAK2 mutation without statistical significance (p=0.172 and 0.094, respectively). But this mutation was not correlated with sex, hemoglobin, platelet count, splenomegaly, increased cellularity of bone marrow, bone marrow fibrosis and vascular complications. Conclusions: The current observation strengthens the specific association between JAK2 mutation and ET. At the diagnosis of ET, identification of JAK2 mutation should be incorporated in foundation for new approaches.

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The Analysis of JAK2 and MPL Mutation as Well as JAK2 SNPs in MPN Patients by MassARRAY Assay.

Blood ◽

10.1182/blood.v114.22.4989.4989 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4989-4989

Author(s):

Su-Jiang Zhang ◽

Hongxia Qiu ◽

Jianyong Li

Keyword(s):

Conflicts Of Interest ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Myeloproliferative Disorders ◽

Molecular Pathogenesis ◽

Significant Difference ◽

Positive Rate ◽

Allele Specific ◽

Polymerase Chain ◽

Distribution Frequency

Abstract Abstract 4989 Introduction Recent studies have shown that JAK2 V617F, MPL W515L/K and JAK2 exon 12 mutations underlie the major molecular pathogenesis of myeloproliferative disorders (MPN). Methods To ascertain the real prevalence of these mutations and the influence of genetic susceptibility in Chinese MPN patients, we applied Allele-Specific Polymerase Chain Reaction (AS-PCR), directly sequencing and MassARRAY assay into our study. Results The positive rate of JAK2 V617F in polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) was 82.0%, 36.6% and 51.1% individually. We also found one ET patient, two PMF patients harboring MPL W515L mutation, and three PV patients harboring JAK2 exon 12 mutations. All of these patients were confirmed as JAK2 V617F negative. Moreover, clinical data demonstrated that PV patients with JAK2 exon 12 mutations had higher hemoglobin and lower age as well as WBC than PV patients with JAK2 V617F. In addition, through analysis of 4 polymorphic loci of JAK2 gene, no significant difference of distribution frequency was found among PV, ET and PMF patients. Distribution frequency of haplotype was not found to have significant difference among PV, ET and PMF patients either. Conclusion We conclude that JAK2 V617F is major molecular pathogenesis in Chinese MPN patients. MPL W515L mutation and JAK2 exon 12 mutations can also be found in JAK2 V617F negative MPN patients. Disclosures No relevant conflicts of interest to declare.

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