Thrombosis History and Relationship With Low Thrombocytosis, Leukocytosis, and Other Characteristics At Diagnosis In 977 Essential Thrombocythemia Patients A Multivariate Analysis Of The Registro Italiano Trombocitemie (RIT)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2829-2829
Author(s):  
Luigi Gugliotta ◽  
Alessandra Iurlo ◽  
Alessia Tieghi ◽  
Gabriele Gugliotta ◽  
Anna Candoni ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Multivariate Analysis ◽  
Jak2 V617f ◽  
Male Gender ◽  
Jak2 V617f Mutation ◽  
Bone Marrow Fibrosis ◽  
History Of ◽  
V617f Mutation ◽  
Marrow Fibrosis

Abstract Background In essential thrombocythemia (ET) patients, history of thrombosis and age over 60 y are validated risk factors for occurrence of thrombosis during the follow-up. Leukocytosis, JAK2 V617F mutation, cardiovascular (CV) general risk factors, and male gender are candidate risk factors for thrombosis. The thrombocytosis, a constitutive abnormality in ET, is associated with both thrombotic and hemorrhagic complications. Aim To evaluate in a large cohort of ET patients the potential relationship between the thrombosis history and the main clinical and biological characteristics at diagnosis, i.e. before any interference of cytoreductive treatment. Methods A cohort of ET patients (PVSG or WHO criteria) of the Registro Italiano Trombocitemie (RIT) was retrospectively analyzed through logistic regression models. Results A total of 977 patients, 387 males and 590 females, presented at diagnosis: median age 56 y (43% with age >60 y), median PLT count 783 x 109/L (33% with low thrombocytosis, <700 x 109/L), median WBC count 8.8 x 109/L (29% with leukocytosis, >10 x 109/L), median HCT 42.6% (high HCT: >47% in 24% of the males and >44% in 23% of the females), CV general risk factors in 69% of cases (one of smoking, hypercholesterolemia, hypertriglyceridemia, hypertension, diabetes, obesity, CV disease, familiarity for thrombosis), bone marrow fibrosis grade 0 in 67% of cases, JAK2 V617F mutation in 56% of the 399 tested patients. The history of thrombosis (arterial in 74% of cases) was reported in 194 (19.9%) patients. The history of thrombosis in univariate analysis was significantly related to: age >60 y (p 0.001), male gender (p 0.009), CV general risk factors (p 0.002), low thrombocytosis (p 0.000), leukocytosis (p 0.003), high HCT (p 0.004), and JAK2 V617F mutation (p 0.008). No relationship was found with bone marrow fibrosis. In multivariate analysis a relationship was confirmed between thrombosis history and age >60 y (p 0.023), male gender (0.046), CV general risk factors (0.039), low thrombocytosis (p 0.004), leukocytosis (0.019), and JAK2 V617F mutation (p 0.033). The rate of thrombosis history in the patients without both low thrombocytosis and leukocytosis (11%, 49/428) resulted significantly lower (p 0.0001) than in the patients with leukocytosis (24%, 54/224), the patients with low thrombocytosis (27%, 71/266), and the patients with both low thrombocytosis and leukocytosis (34%, 20/59). Conclusion In this cohort of ET patients the rate of thrombosis history in multivariate analysis is significantly related to various clinical and biological characteristics at diagnosis, including low thrombocytosis (PLT <700 x 109/L), leukocytosis (WBC >10 x 109/L), JAK2 V617F mutation, age >60 y, male gender, and CV general risk factors. Acknowledgment this study was partially supported by the GIMEMA Foundation (Promotor of the RIT) and by the AIL Foundation. Disclosures: Gugliotta: SHIRE Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Thrombosis History and Relationship with Low Thrombocytosis, Leukocytosis, and Jak2 V617F Mutation In A Cohort of 977 Patients with Essential Thrombocythemia (ET): Preliminary Report of the Registro Italiano Trombocitemia(RIT),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3836-3836
Author(s):  
Luigi Gugliotta ◽  
Alessia Tieghi ◽  
Alessandra Iurlo ◽  
Anna Candoni ◽  
Giorgina Specchia ◽  
...  
Keyword(s):  
Risk Factors ◽  
Univariate Analysis ◽  
Jak2 V617f ◽  
Male Gender ◽  
Jak2 V617f Mutation ◽  
History Of ◽  
V617f Mutation ◽  
Group 2 ◽  
Wbc Count ◽  
Age Over 60

Abstract Abstract 3836 Background. In essential thrombocythemia (ET) patients history of thrombosis and age over 60 y are validated risk factors for thrombosis; the thrombocytosis is a constitutive abnormality associated with both thrombotic and hemorrhagic risk; JAK2 V617F mutation, leukocytosis, and male gender are candidate thrombotic risk factors. Aims. To evaluate in ET patients clinical-biological characteristics at diagnosis and their relationship with thrombosis occurrence before and after diagnosis. Methods. A cohort of ET patients of the Registro Italiano Trombocitemia (RIT) was retrospectively analysed. This preliminary report in detail considers data on thrombosis history. Results. A total of 977 patients, 387 males and 590 females, presented at diagnosis: median age 55 y, median PLT count 783 × 109/L, median WBC count 8.8 × 109/L, median Hb 14.1 g/dL, bone marrow fibrosis (grade >0) in 33% of cases, history of thrombosis in 189 cases (19.3%). The patients at high risk (age over 60 y and/or history of thrombosis) were 511 (52 %). The thrombosis history in univariate analysis was significantly related to: age over 60 y (p 0.001), male gender (p 0.045), low thrombocytosis (PLT <783 x109/L, p 0.001), leukocytosis (WBC >8.8 x109/L, p 0.01), and JAK2 V617F mutation (p 0.006). No relationship was found with the bone marrow fibrosis. The 977 patients, when both PLT count and WBC count at diagnosis were considered, were subdivided in four groups: group 1: 202 pts with low thrombocytosis and leukocytosis; group 2: 270 pts with low thrombocytosis and no leukocytosis; group 3: 272 pts with high thrombocytosis and leukocytosis; group 4: 197 pts with high thrombocytosis and no leukocytosis. In those patients, the thrombosis history was: 26.7% in the group 1(both risk factors); 24.1% in the group 2 (PLT risk factor); 20.2% in the group 3 (WBC risk factor); 7.6% in the group 4 (no risk factors). The rate of thrombosis history in patients with one or two of these risk factors was significantly (p 0.001) higher than in patients with no risk factors. The thrombotic events during the follow up (4088 pt-y) are still object of analysis. Conclusion. In this cohort of ET patients the rate of thrombosis history in univariate analysis was related to age over 60 y. Moreover, a significant relationship was found with PLT count at diagnosis below the median value (783 x109/L), WBC count at diagnosis over the median value (8.8 x109/L), JAK2 V617F mutation, and male gender. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The mortality outcomes and survival pattern of patients of Myeloproliferative Neoplasms in Malaysia

2021 ◽  
Author(s):  
yeeyee yap ◽  
Jameela Sathar ◽  
Kian Boon Law ◽  
MPN registry working group
Keyword(s):  
Diabetes Mellitus ◽  
Bone Marrow ◽  
Overall Survival ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Bone Marrow Fibrosis ◽  
Survival Pattern ◽  
V617f Mutation ◽  
Marrow Fibrosis

Abstract Background: The prognostication of myeloproliferative neoplasm (MPN) has always been challenging even in the advent of Janus kinase 2 (JAK2 V617F) molecular studies. The survival pattern of MPN in a developing country such as Malaysia is still undetermined.Materials and Methods: This was a retrospective study using information from 774 patients from the National MPN Registry conducted from the year 2009 to 2015 in Malaysia. Patients with the diagnosis of essential thrombocythaemia (ET), polycythaemia vera (PV), primary myelofibrosis (PMF) and unclassified MPN (MPN-U) were included. Survival data were traced until December 2018. Results: The cohort consisted of 42.0% ET, 41.0% PV, 8.9% PMF and 8.1% MPN-U, with 48.8% Malay, 39.1% Chinese, 7.1% Indian, 5.0% Others. The subtypes analysis revealed that male MPNs was more than female MPNs except in ET. The Chinese ethnicity was associated with the highest incidence of ET. The mortality rate was the highest in PMF followed by MPN-U then PV and ET (p<0.0001). Survival analysis revealed that the overall survival differed significantly according to characteristics such as sex, sub-types, JAK2 V617F mutation, bone marrow fibrosis, presence of splenomegaly, diabetes mellitus, hypertension, and bleeding manifestation. Cox regression analysis identified age, haemoglobin level, sex, and subtype as a significant risk factor for mortality outcome. Conclusion: Patients with ET had the slightly better OS while PMF had the worst OS. This is in conjunction with low haemoglobin, worsening bone marrow fibrosis, splenomegaly, diabetes mellitus, hypertension and bleeding. JAK2 V617F mutation was seemingly resulting in inferior overall survival especially in ET and PMF. The survival outcome of the MPN registry is instrumental for future policy development of effective healthcare in Malaysia.

scholarly journals A rare atypical chronic myeloid leukemia BCR-ABL1 negative with concomitant JAK2 V617F and SETBP1 mutations: a case report and literature review

2020 ◽  
Vol 11 ◽  
pp. 204062072092710
Author(s):  
Tianqi Gao ◽  
Changhui Yu ◽  
Si Xia ◽  
Ting Liang ◽  
Xuekui Gu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Targeted Therapy ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Jak2 V617f ◽  
Next Generation ◽  
Bone Marrow Fibrosis ◽  
Atypical Chronic Myeloid Leukemia ◽  
Generation Sequencing ◽  
Marrow Fibrosis

Atypical chronic myeloid leukemia (aCML) BCR-ABL1 negative is a rare myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) for which no standard treatment currently exists. The advent of next-generation sequencing has allowed our understanding of the molecular pathogenesis of aCML to be expanded and has made it possible for clinicians to more accurately differentiate aCML from similar MDS/MPN overlap syndrome and MPN counterparts, as MPN-associated driver mutations in JAK2, CALR, or MPL are typically absent in aCML. A 55-year old male with main complaints of weight loss and fatigue for more than half a year and night sweats for more than 2 months was admitted to our hospital. Further examination revealed increased white blood cells, splenomegaly, and grade 1 bone marrow fibrosis with JAK2 V617F, which supported a preliminary diagnosis of pre-primary marrow fibrosis. However, in addition to JAK2 V617F (51.00%), next-generation sequencing also detected SETBP1 D868N (46.00%), ASXL1 G645fs (36.09%), and SRSF2 P95_R102del (33.56%) mutations. According to the 2016 World Health Organization diagnostic criteria, the patient was ultimately diagnosed with rare aCML with concomitant JAK2 V617F and SETBP1 mutations. The patient received targeted therapy of ruxolitinib for 5 months and subsequently an additional four courses of combined hypomethylating therapy. The patient exhibited an optimal response, with decreased spleen volume by approximately 35% after therapy and improved symptom scores after therapy. In diagnosing primary bone marrow fibrosis, attention should be paid to the identification of MDS/MPN. In addition to basic cell morphology, mutational analysis using next-generation sequencing plays an increasingly important role in the differential diagnosis. aCML with concomitant JAK2 V617F and SETBP1 mutations has been rarely reported, and targeted therapy for mutated JAK2 may benefit patients, especially those not suitable recipients of hematopoietic stem cell transplants.

Relation between JAK2 V617F Mutation and Chronic Myeloproliferative Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4638-4638
Author(s):  
Zhjian Xiao ◽  
Yue Zhang ◽  
Jianxiang Wang ◽  
Yushu Hao
Keyword(s):  
Bone Marrow ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Hemoglobin Level ◽  
Jak2 V617f Mutation ◽  
Control Group ◽  
Mutation Load ◽  
Chronic Myeloproliferative Disorders ◽  
V617f Mutation ◽  
Secondary Myelofibrosis

Abstract The chronic myeloproliferative disorders (cMPDs) are a group of clonal malignant tumors of the hematological system, and derived from the pluripotential hemopoietic stem cells, manifested as the proliferation of one or more series of cells in the bone marrow as well as the occurrence of excessive mature or naive cells in the peripheral blood. It was reported by several research groups that there was the acquired JAK2 V617F mutation in the majority of the PV patients and in a part of the ET or PMF patients, which provided the new ideas for the investigation of the pathogenesis of BCR/ABL- cMPDs. In the present study, the JAK2 V617F mutation was detected in a larger collection of Chinese cMPD patients, to give a picture of the incidence of JAK2 V617F mutation in the Asian pollutions. A total of 523 patients with the cMPDs, including 278 males and 245 females, were analyzed. Their median age was 50 years old (7 to 83 years old). According to the WHO diagnostic criteria, among the 523 patients were 88 cases of CML at the chronic phase (including 59 males and 29 females with a median age of 40 years old), 25 of CML complicated with myelofibrosis, 116 of PV (64 males and 52 females; a median age of 53; among them were six cases of PV with the secondary myelofibrosis), 153 of ET (63 males and 91 females; a median age of 50; 15 cases of ET with the secondary myelofibrosis), 142 of PMF (71 males and 71 females; a median age of 53.5), four of unclassified CMPD (CMPD-U) (2 males and 2 females; a median age of 60), seven of high eosinophil syndrome (HES) (6 males and 1 female; a median age of 32), and 13 of chronic eosinophilic leukemia (13 males; a median age of 34). In addition, 140 of healthy adults were included in the control group. Allele-specific PCR (ASP) was applied to identify JAK2 V617F mutation, the mutation status was analyzed by PCR-RFLP, and the results were confirmed by sequence analysis. The mutation load was calculated by the ratio of T/G. Then explore the correlation between the allele load and the clinical, hematologic features. To those without JAK2 V617F, MPL W515L mutation was analyzed. JAK2 V617F was detected in 66%(346/523) of all patients (94%(109/116) in PV, 79%(122/153) in ET, 78%(111/142) in PMF, 75%(3/4) in CMPD-U and 14%(1/7) in HES).Majority of patients carried JAK2 V617F mutation were heterozygous, homozygote was found in only 5 cases (4 in PV and 1 in ET). The mutation load in majority patients (71.5%) was low, PV>ET>MF when compared with mutation load (p=0.003). Hemoglobin level was significantly related to high mutation load in PV (p=0.033, r=0.203). Bone marrow megakaryocyte counts were found to be marked increased in ET with high JAK2 V617F loads (P=0.024, r=0.205), and hepatomegaly in PMF was also significiently associated with high JAK2 V617F mution load (p=0.003, 0.001)(p=0.001, r=0.315). Oue data showed that Majority of cMPD patients, especialy with PV, carried JAK2 V617F mutation, but JAK2 V617F was absent in CML; 98% of JAK2 V617F mutation occurs in a heterozygous status, only 4 patients with PV and 1 with ET were homozygouse.; PV> ET> MF when compared with mutation load. High JAK2 V617F loads were found to be significantly associated with higher hemoglobin level in PV and higher bone marrow megakaryocyte counts in ET; The correlation between hepatomegaly and JAK2 V617F mutation load were also found in PMF.

TGFb1 Antagonist Inhibits Fibrosis in a Murine Model of Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 605-605 ◽  
Author(s):  
Rajasekhar NVS Suragani ◽  
Pedro A. Martinez ◽  
Sharon M Cawley ◽  
Robert Li ◽  
Robert Scott Pearsall ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Murine Model ◽  
Jak2 V617f ◽  
Mutant Mice ◽  
Wild Type ◽  
Employment Equity ◽  
Bone Marrow Fibrosis ◽  
Equity Ownership ◽  
Marrow Fibrosis

Abstract Introduction: Myelofibrosis (MF) is a clonal stem cell disorder that originates from acquired mutations in the hematopoietic stem cells leading to abnormal kinase signaling, cell proliferation, cytokine expression, and splenomegaly and ultimately bone marrow (BM) fibrosis. Primary myelofibrosis (PMF), post-polycythemia vera (PV) MF and post-essential thrombocythemia MF are categorized under MF with overlapping disease phenotypes including progression to BM fibrosis. A genetic mutation in Janus kinase 2 (V617F) was identified as causative in ~95% PV, and ~50% of ET and PMF patients. Currently, treatment of MF patients with a JAK2 inhibitor offers symptomatic benefit, but does not alter the natural history of the disease or improve BM fibrosis. It is known that TGFβ1 is a critical regulator of fibrosis in many disease states. Elevated TGFβ1 levels were reported to be important for fibrosis in patients with MF. We hypothesize that inhibition of TGFβ1 signaling may prevent fibrosis and help reduce secondary morbidities associated with disease in MF patients. Therefore, we evaluated this hypothesis using a TGFβ1 antagonist in a murine model of MF. Methods: Transgenic JAK2 (V617F) mutant mice (MF model) and age-matched wild-type controls were used in the studies. Mice were dosed twice weekly with TGFβ1 antagonist (10 mg/kg). Complete blood counts (CBC), serum TGFβ1, bone metabolism and inflammatory cytokines levels were determined at different ages (2-12 months) during disease progression. Bone marrow and spleen cells were analyzed for different cell lineages by flow cytometry. Tissue sections were stained with H&E and reticulin to determine cellularity or degree of fibrosis respectively. Results: To understand the onset and progression of MF disease in JAK2 (V617F) mice, we initially analyzed the CBC and degree of fibrosis at various ages (2, 3, 4, 5, 8, 10 and 12 months) and compared the data with wild-type mice. These data were then correlated with the levels of TGFβ1 and other cytokines. As expected, red blood cells (RBC) and platelets were elevated in JAK2 mutant mice at all ages compared to wild-type mice, although a trend towards a progressive increase was observed between 2 to 5 months followed by a decrease from 8 to 14 months. Bone marrow fibrosis was detected starting at 5 months and worsened with age. JAK2 mutant mice displayed splenomegaly that increased as the disease progressed. Interestingly, serum levels of TGFβ1, TGFβ3 and bone metabolism cytokines (OPG, OPN, aFGF and Trance) displayed an increase at earlier ages (2-5 months) compared to the latter ages, a trend similar to RBC levels. These levels peaked during the initiation of fibrosis at 5 months. In contrast, inflammatory cytokines (such as IL6, IL-1β, and TNFα) were elevated at later ages consistent with disease progression. We initiated treatment with TGFβ1 antagonist in JAK2 (V617F) mice (N=8/treatment group) at 4 months of age, the age corresponding to elevated serum TGFβ1 levels and prior to the onset of fibrosis (at 5 months of age). Following 6 months of treatment, vehicle (VEH) treated JAK2 mutant mice displayed elevated RBC (+37.1%, P<0.001), platelets (+74.5%, P<0.001) and spleen weights (+9.5 fold, P<0.001) compared to wild-type mice. BM and spleen sections from VEH treated JAK2 mutant mice revealed severe fibrosis. TGFβ1 antagonist treatment of JAK2 mice displayed moderate effect on RBC (-8.4%, N.S) without any effect on platelet counts compared to VEH treatment. Flow-cytometry identified a reduced proportion of Ter119+ erythroid precursors in BM and spleen (-15%, P<0.05) and no change in CD41+ megakaryocytes. TGFβ1 antagonist treated mice displayed reduced spleen weights (-29%, P<0.01), and marked reduction in fibrosis in bone marrow (Figure) and spleen sections compared to VEH. Consistent with the reduction in fibrosis, TGFβ1 antagonist treated JAK2 mice displayed reduced IL-6 levels (-48.9%, P<0.05) compared to VEH treatment. Conclusion: Together, these data demonstrated that TGFβ1 levels were correlated with bone marrow fibrosis in a murine model of MF disease, and its inhibition using TGFβ antagonist reduces fibrosis, splenomegaly and inflammation in this murine model of myelofibrosis. Figure 1. Figure 1. Disclosures Suragani: Acceleron Pharma Inc: Employment, Equity Ownership, Patents & Royalties: No royalties. Martinez:Acceleron Pharma: Employment. Cawley:Acceleron Pharma Inc: Employment. Li:Acceleron Pharma: Employment, Equity Ownership. Pearsall:Acceleron Pharma Inc: Employment, Equity Ownership, Patents & Royalties. Kumar:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties.

scholarly journals The implication of identifying JAK2 V617F in myeloproliferative neoplasms and myelodysplastic syndromes with bone marrow fibrosis

2008 ◽  
Vol 1 (2) ◽  
pp. 111-117 ◽  
Author(s):  
Randall J. Olsen ◽  
Cherie H. Dunphy ◽  
Dennis P. O’Malley ◽  
Lawrence Rice ◽  
April A. Ewton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

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 ◽  
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.

The Hematopoietic Stem Cell Compartment Is Different in Polycythemia Vera and Idiopathic Myelofibrosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 259-259 ◽  
Author(s):  
Chloe James ◽  
Frederic Mazurier ◽  
Ronan Chaligne ◽  
Sabrina Dupont ◽  
Francois Delhommeau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
B Lymphocytes ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
V617f Mutation ◽  
Myeloid Progenitors

Abstract X-linked clonality studies showed that myeloproliferative disorders derive from an abnormal hematopoietic stem cell (HSC). This has been recently confirmed by studies showing that the JAK2 V617F mutation was present in multipotent cells from patients with Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primitive Myelofibrosis (PMF). How one unique mutation could give rise to three different diseases remains unexplained and we hypothesized that the HSC compartment may be different in PV and PMF. To investigate whether the V617F mutation occurs in HSCs in PV and PMF, and whether the HSC compartments are different in these 2 diseases, we performed simultaneously two types of experiments: Myeloid, B, and NK in vitro differentiation assays and Repopulation of immune-deficient NOD/SCID mice with human JAK2 V617F CD34+ cells followed by analysis of the frequency of JAK2 V617F clones. We first confirmed that the JAK2 V617F mutation is present in HSCs, enabling long-term (15 weeks) in vivo hematopoietic reconstitution, both in PV and PMF patients. Nevertheless, we found marked differences between PV and PMF samples. Indeed, the frequency of JAK2 V617F lympho-myeloid progenitors was much higher in MF (6 PMF and one post PV-MF) than in PV patients (n = 9) (87.2% +/− 31.3 vs 21% +/− 21.1 respectively). Similarly, most of the human myeloid progenitors present in mice transplanted with CD34+ cells from MF patients (n = 7) 15 weeks post-transplantation were JAK2 V617F. On the contrary, human myeloid progenitors were predominantly JAK2 WT after transplantation of PV CD34+ cells (9 patients). To determine if the mutation was present in HSC able to differentiate into B-lymphocytes in PV and MF, we sorted and genotyped the fraction of B-lymphocytes (CD45+CD19+) that differentiated in the bone marrow of mice. In 5 mice transplanted with PV CD34+ cells, the fraction of B-cells was always JAK2 WT whereas in 2 out of 3 mice transplanted with MF CD34+ cells, B-lymphocytes were JAK2 V617F. To determine if the mutation was present in HSC capable of very long-term reconstitution in PV and PMF, we looked for the presence of long-term culture-initiating cells (LTC-IC) among human CD34+ cells isolated from the bone marrow of NOD/SCID mice (2 PV, 3 MF) 15 weeks after transplantation. In 2 mice transplanted with PMF CD34+ cells, the majority of LTC-ICs (70/70 and 95/166) were JAK2 V617F. On the contrary, in 3 mice reconstituted with PV CD34+ cells, most of the LTC-ICs were JAK2 WT (23/23, 4/4 and 126/168) although we could find some LTC-ICs that were JAK2 V617F, demonstrating that in PV also, the JAK2 V617F mutation is present in Long Term-HSC. Taken together these results demonstrate that the JAK2 V617F mutation is present in a small subset of HSCs in PV patients, whereas in MF, the vast majority of HSCs is JAK2 V617F. This suggests that these two diseases are two stages of the same pathology and that in MF the JAK2 V617F HSCs have acquired a proliferative advantage on JAK2 WT HSCs and thus have invaded the hematopoietic system.

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