Novel, Potent and Selective JAK2 Inhibitors.

Abstract Abstract 3777 Poster Board III-713 The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and from primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative disorders and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild type enzymes by novel small molecule inhibitors, which act in an ATP-competitive manner. The profile of a lead compound from this class will be presented that displays more than twenty-fold selectivity towards JAK2 within the JAK family, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, the inhibitor exhibited good oral bioavailability and is efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model as well as polycythemia and extramedullary erythropoiesis in mouse and rat models. Disclosures: Radimerski: Novartis: Employment, Equity Ownership. Baffert:Novartis: Employment. Regnier:Novartis: Employment. De Pover:Novartis: Employment. Pissot:Novartis: Employment. Gerspacher:Novartis: Employment. Brueggen:Novartis: Employment. Tavares:Novartis: Employment. Blasco:Novartis: Employment. Ledieu:Novartis: Employment. Nolan:Novartis: Employment. Ruetz:Novartis: Employment. Chene:Novartis: Employment. Erdmann:Novartis: Employment. Drueckes:Novartis: Employment. Furet:Novartis: Employment. Lang:Novartis: Employment. Trappe:Novartis: Employment. Vangrevelinghe:Novartis: Employment. Wartmann:Novartis: Employment. Hofmann:Novartis: Employment.

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Evaluation of the JAK2 V617F gene mutation in myeloproliferative neoplasms cases: a one-center study from Eastern Anatolia

Turkish Journal of Biochemistry ◽

10.1515/tjb-2018-0054 ◽

2019 ◽

Vol 44 (4) ◽

pp. 492-498

Author(s):

Gonca Gulbay ◽

Elif Yesilada ◽

Mehmet Ali Erkurt ◽

Harika Gozukara Bag ◽

Irfan Kuku ◽

...

Keyword(s):

Blood Cell ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Hematological Parameters ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Myeloproliferative Disorders ◽

Jak2 V617f Mutation ◽

V617f Mutation ◽

The Difference

AbstractObjectiveDetection ofJAK2V617F in myeloproliferative neoplasms (MPNs) is very important in both diagnosis and disease progression. In our study, we investigated the frequency ofJAK2V617F mutation in patients with myeloproliferative disorders.MethodsWe retrospectively reviewed the records of 720 patients (174 females and 546 males) who were tested for JAK2 V617F mutation from January 2007 to December 2017.ResultsIn our patients were determined 22.6%JAK2V617F mutation. 33.3% in women, 19.2% in men have been positive forJAK2V617F mutation. In our studyJAK2V617F present in 48.6% of essential thrombocythemia, 80.5% of polycythemia rubra vera (PV), 47.5% of primary myelofibrosis, 10% of MPNs, unclassifiable, 0.8% of others. We also investigated the difference in hematological parameters [white blood cell, hemoglobin (Hb), hematocrit (HCT), red blood cell distribution widths (RDW) and platelets count (PLT)] betweenJAK2V617F positive andJAK2V617F negative patients.ConclusionsInvestigation of the JAK2 V617F mutation is very important in cases of MPNs. In our study JAK2 V617F mutation was higher in PV, essential thrombocythemia, and primary myelofibrosis patients. However, there were significant differences in Hb, HCT, RDW and PLT levels in mutation-positive patients.

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Two Classes of Progenitor Cells in Patients with Myeloproliferative Disorders Are Capable of Generating JAK2V617F+CD31+CD144+ Endothelial Cells.

Blood ◽

10.1182/blood.v110.11.261.261 ◽

2007 ◽

Vol 110 (11) ◽

pp. 261-261

Author(s):

Selcuk Sozer ◽

Takefumi Ishii ◽

Wei Zhang ◽

Jiapeng Wang ◽

Mingjiang Xu ◽

...

Keyword(s):

Endothelial Cells ◽

Progenitor Cells ◽

Mononuclear Cells ◽

Vascular Endothelial Cells ◽

Inverse Correlation ◽

Primary Myelofibrosis ◽

Myeloproliferative Disorders ◽

Growth Media

Abstract Patients with myeloproliferative disorders (MPD) are at a high risk of developing thrombotic events. We hypothesize that one of the contributory factors to this thrombotic tendency is the involvement of vascular endothelial cells (EC) by the malignant process. In vitro and in vivo assays were used to determine the involvement of EC in patients with MPD. Endothelial progenitor cells (EPC) were assayed from the peripheral blood (PB) mononuclear cells (MNCs) of 3 normal controls (NC) and 16 patients with MPD (12 polycythemia vera (PV), 4 primary myelofibrosis (PMF). MNC were cultured for 2 days in EC growth media on fibronectin(FN)-coated plates. The non-adherent cells were then harvested and transferred to a secondary FN-coated plate for additional 5–14 days. EC colonies were identified by their morphological appearance. The colonies were plucked and analyzed for PECAM-1(CD31), VE-Cadherin(CD144), VEGFR-2, vWF, Endoglin(CD105), ULEX-1, CD45, CD14 by flow cytometry and acetylated LDL(Ac-ADL) uptake. EC colonies were CD31+CD144+VEGFR2+ULEX-1+vWF+CD105+CD45+CD14+ and capable of taking up Ac-LDL and when exposed to TNF-α and IL-1β, expressing ICAM(CD54) and E-selectin(CD62e). MPD MNC formed fewer numbers of EC colonies than normal MNC (31.1±34.2 vs 78.8±28.9; p<0.01) and required more prolonged periods of culture (14 vs 5days). MPD EC colonies were also analyzed for JAK2V617F(JAK2VF) by nested-PCR. 74.6% of MPD EC colonies were homozygous(homo) JAK2VF, 14.9% were heterozygous(hetero) JAK2VF and 10.4% were wild type(wt) JAK2. Interestingly, MNCs from JAK2VF−MPD(148±47) formed greater numbers of EC colonies than NC MNC (78.8±28.9; p≤0.01). MNC from patients with a high burden of JAK2VF alleles (10.3±18.5; p<0.01) formed fewer EC colonies than NC or patients with a low burden of JAK2VF (65.9±28.15; p≤0.01). These EPC assayed in vitro which produced cells with both myeloid and endothelial markers are likely due either to contamination with JAK2VF myeloid cells or the result of the transdifferentiation of myeloid progenitor cells into EC (Bailey A, et al. PNAS.2006,103:13156). The inverse correlation between the JAK2VF burden and the ability of MPD MNC to form EC colonies is possibly a consequence of the increased sensitivity of EC to apoptosis due to the constitutive activation of JAK2 (Neria F, et al. Am J Physiol Cell Physiol.2007, 292:1123). In order to assay for more primitive EPC, 2 cord blood, and 16 JAK2VF+ MPD CD34+ (10 PV, 6 PMF) cells were transplanted into sublethally irradiated NOD/SCID mice. After 8 weeks, EC-rich organs (heart, lung, liver, vessels) were harvested, single cell suspensions were positively selected for either human(h) CD31+or hCD144+ cells by immunomagnetic cell sorting and analyzed for hVEGFR2, CD144, vWF, CD45, CD14 mRNA expression and JAK2VF. These CD31+or CD144+ cells contained transcripts for CD144, vWF, VEGFR2 but not CD45 and CD14. In 77.7% of the cases the hCD31+ or hCD144+ cells were homo JAK2VF, 5.5% were hetero JAK2VF and 16.6% were wt JAK2 and these CD31+or CD144+ cells composed ≤1% of the cells within the respective tissues. hCD144+ cells were also cultured with EC growth media for 7 days and displayed EC morphology and were shown to contain JAK2VF+ cells. These CD31+CD144+JAK2VF+CD14−CD45−cells likely represent the progeny of a malignant EPC which is distinct from an HSC. The involvement of EC by the malignant process in MPD might contribute to the development of thrombosis in MPD.

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Combination approach to diagnosis and treatment of an elderly patient with chronic Ph-negative myeloproliferative neoplasm and concomitant surgical pathology. Clinical observation

MD-Onco ◽

10.17650/2782-3202-2021-1-1-61-65 ◽

2021 ◽

Vol 1 (1) ◽

pp. 61-65

Author(s):

Yu. E. Ryabukhina ◽

P. A. Zeynalova ◽

O. I. Timofeeva ◽

F. M. Abbasbeyli ◽

T. V. Ponomarev ◽

...

Keyword(s):

Elderly Patient ◽

Essential Thrombocythemia ◽

Early Stage ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Left Femur ◽

Hematopoietic Stem ◽

Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.

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Aktualitások a primer myelofibrosis ellátásában

Orvosi Hetilap ◽

10.1556/650.2016.30531 ◽

2016 ◽

Vol 157 (39) ◽

pp. 1547-1556

Author(s):

Zsófia Simon ◽

Imelda Marton ◽

Zita Borbényi ◽

Árpád Illés

Keyword(s):

Treatment Approach ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Spleen Volume ◽

Novel Therapy ◽

Jak2 Inhibitor ◽

Chronic Myeloproliferative Neoplasms ◽

Associated Symptoms ◽

Modifying Effect ◽

Disease Modifying

Primary myelofibrosis is one of the Philadelphia negative chronic myeloproliferative neoplasms. It is a rare disease featured by cytopenias and hepatosplenomegaly. Although the etiology of the disease is still unknown, our knowledge about its pathology and prognosis has been improving in the last few years. Furthermore, the JAK2 inhibitor ruxolitinib has become available in Hungary since 2015. Beside its high efficacy in spleen volume and in reduction of myelofibrosis-associated symptoms, this novel therapy also exerts a disease-modifying effect and, therefore, ruxolitinib may improve the life expectancy too. Treatment approach of myelofibrosis has been changed these years, which gives a reason for this summary. Orv. Hetil., 2016, 157(39), 1547–1556.

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CHRONIC MYELOPROLIFERATIVE NEOPLASMS: A COLLABORATIVE APPROACH

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2010.017 ◽

2010 ◽

Vol 2 (2) ◽

pp. e2010017

Author(s):

Lisa Pieri ◽

Paola Guglielmelli ◽

Alessandro Maria Vannucchi

Keyword(s):

Acute Leukemia ◽

Clinical Course ◽

Myeloproliferative Neoplasms ◽

Clinical Manifestations ◽

Primary Myelofibrosis ◽

The Other ◽

Collaborative Approach ◽

Chronic Myeloproliferative Neoplasms ◽

Key Issues ◽

Oriented Approach

The classic chronic myeloproliferative neoplasms (MPN) include different entities that pose significant challenges for their optimal diagnosis, treatment and overall management. Polycythemia Vera and Essential Thrombocythemia are the most common among chronic myeloproliferative neoplasms (MPNs); major causes of morbidity and mortality are represented by arterial and venous thrombosis, as well as evolution to myelofibrosis or transformation to acute leukemia. However, survival is only minimally affected. Therapy aims at reducing the rate of thrombosis without increasing the risk of hematologic transformation which could be caused by exposure to cytotoxic drugs. On the other hand, survival is significantly reduced in primary myelofibrosis, and the clinical manifestations may be disabling. In the absence of therapies with the potential of curing the disease, a careful risk-oriented approach is employed for stratifying patients to the most appropriate, currently available, therapeutic options. In this brief review, we will discuss some of the key issues that can arise along the clinical course of MPNs and require an integrated, strictly patient-oriented, approach.

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Bone marrow megakaryocytic activation predicts fibrotic evolution of Philadelphia-negative myeloproliferative neoplasms.

Haematologica ◽

10.3324/haematol.2020.264143 ◽

2020 ◽

pp. 0-0

Author(s):

Mattia Schino ◽

Vincenzo Fiorentino ◽

Elena Rossi ◽

Silvia Betti ◽

Monica Di Cecca ◽

...

Keyword(s):

Bone Marrow ◽

Myeloproliferative Neoplasms ◽

Rapid Evolution ◽

Progression Free Survival ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Serum Levels ◽

Chronic Myeloproliferative Neoplasms ◽

Calr Mutations ◽

Wbc Count

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have been traditionally considered as indistinctly slowly progressing conditions; recent evidence proves that a subset of cases have a rapid evolution, so that MPNs’ prognosis needs to be personalized. We identified a new morphological parameter, defined as Megakaryocytic Activation (M-ACT) based on the coexistence of megakaryocytic emperipolesis, megakaryocytes (MK) clusters formation and evidence of arrangement of collagen fibers around the perimeter of MK. We retrospectively analyzed the bone marrow biopsy of two MPNs cohorts of patients with polycythemia (PV) (n=64) and non-PV patients [including essential thrombocythemia (ET), and early/prefibrotic primary myelofibrosis (PMF)] (n=222). M-ACT showed a significant correlation with splenomegaly, white blood cell (WBC) count, and LDH serum levels in both groups, with JAK2 V617F allele burden in PV patients, and with CALR mutations, and platelet count in non-PV patients. Progression-free survival, defined as PV-to-secondary MF progression and non-PV-to-overt PMF, was worse in both PV and early/prefibrotic PMF patients with M-ACT in comparison to those without M-ACT (P<.0001). Interestingly, M-ACT was not found in the subgroup of ET patients. In conclusion, M-ACT can be helpful in the differential diagnosis of MPNs and can represent a new morphologic parameter with a predictive value for progression of MPNs.

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TG101348, a potent, highly selective JAK2 inhibitor, inhibits colony formation in stem cells from polycythemia vera patients and prevents JAK2V617F-mediated splenomegaly and death in a mouse model

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7031 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7031-7031 ◽

Cited By ~ 3

Author(s):

J. Hood ◽

J. Doukas ◽

M. Martin ◽

G. Noronha ◽

C. Jamieson ◽

...

Keyword(s):

Polycythemia Vera ◽

Colony Formation ◽

Cell Model ◽

Myeloproliferative Disorders ◽

Myeloid Metaplasia ◽

Jak2 Inhibitor ◽

Potent Inhibition ◽

Pharmaceutical Properties ◽

Myelofibrosis With Myeloid Metaplasia

7031 Background: The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia has been strongly linked to an activating mutation of JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino acid residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases. Methods: In order to address this unmet clinical need we designed, synthesized and performed preclinical evaluations on a series of structurally novel compounds optimized for JAK2 inhibition. Results: TG101348, a compound which potently inhibits JAK2V617F enzymatically and in human cells, was selected as a clinical development candidate from this medicinal chemistry campaign. TG101348 displays remarkable kinase specificity as shown by 83X selectivity versus JAK3 and potent inhibition of <2% of the kinases evaluated in a commercial, phylogenetically diverse panel of 212 kinases. TG101348 potently inhibits erythroid colony formation in patient-derived cells from polycythemia patients at doses 2–3X lower than in normal control patients. Consistent with this observation TG101348 inhibits JAK2-driven STAT5 phosphorylation, cell proliferation and cell survival in JAK2V617F-expressing cell lines. In vivo, TG101348 exhibits promising pharmacokinetic profiles in species ranging from mouse to monkey including oral availabilities >20%, and half-lives consistent with once or twice daily dosing. TG101348 reduces the number of circulating mutant JAK2 cells, inhibited splenomegaly and improved survival without significantly impacting normal hematocrit in an aggressive JAK2-driven circulating cell model of disease in rodents. Conclusion: TG101348 has considerable potential for the treatment of JAK2- driven myeloproliferative disorders based on its promising preclinical potency, selectivity and pharmaceutical properties. [Table: see text]

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Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

Journal of Experimental Medicine ◽

10.1084/jem.20151323 ◽

2015 ◽

Vol 212 (11) ◽

pp. 1833-1850 ◽

Cited By ~ 86

Author(s):

Jasper Mullenders ◽

Beatriz Aranda-Orgilles ◽

Priscillia Lhoumaud ◽

Matthew Keller ◽

Juhee Pae ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Myeloproliferative Disorders ◽

Extramedullary Hematopoiesis ◽

Chromatin Accessibility ◽

Early Event ◽

Cohesin Complex ◽

Hematopoietic Stem ◽

Myeloid Metaplasia ◽

Tumor Suppressive Function

The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy.

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Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature

Case Reports in Hematology ◽

10.1155/2012/875039 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6

Author(s):

Diana O. Treaba ◽

Salwa Khedr ◽

Shamlal Mangray ◽

Cynthia Jackson ◽

Jorge J. Castillo ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cell Lymphoma ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Chronic Myeloproliferative Neoplasms ◽

Mantle Cell ◽

Lymphoid Aggregates ◽

Acute Myeloid

Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML. The small lymphoid aggregates noted in his bone marrow were neoplastic in nature and represented bone marrow involvement by a CD5-negative mantle cell lymphoma (MCL) that presented without any associated lymphadenopathy. We reviewed the English medical literature to identify a single case report of simultaneous association of AML and a MCL in the bone marrow. The unusual association presented here suggests an increase in observer awareness to apparently benign lymphoid aggregates in chronic myeloproliferative neoplasms.

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Changing Concepts of Diagnostic Criteria of Myeloproliferative Disorders and the Molecular Etiology and Classification of Myeloproliferative Neoplasms: From Dameshek 1950 to Vainchenker 2005 and Beyond

Acta Haematologica ◽

10.1159/000358580 ◽

2014 ◽

Vol 133 (1) ◽

pp. 36-51 ◽

Cited By ~ 18

Author(s):

Jan Jacques Michiels ◽

Zwi Berneman ◽

Wilfried Schroyens ◽

Hendrik De Raeve

Keyword(s):

Bone Marrow ◽

Polycythemia Vera ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Myeloproliferative Disorders ◽

Jak2v617f Mutation ◽

Wild Type ◽

Mutation Load ◽

Molecular Etiology ◽

Calr Mutations

The Polycythemia Vera Study Group (PVSG) and WHO classifications distinguished the Philadelphia (Ph1) chromosome-positive chronic myeloid leukemia from the Ph1-negative myeloproliferative neoplasms (MPN) essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) or primary megakaryocytic granulocytic myeloproliferation (PMGM). Half of PVSG/WHO-defined ET patients show low serum erythropoietin levels and carry the JAK2V617F mutation, indicating prodromal PV. The positive predictive value of a JAK2V617F PCR test is 95% for the diagnosis of PV, and about 50% for ET and MF. The WHO-defined JAK2V617F-positive ET comprises three ET phenotypes at clinical and bone marrow level when the integrated WHO and European Clinical, Molecular and Pathological (ECMP) criteria are applied: normocellular ET (WHO-ET), hypercellular ET due to increased erythropoiesis (prodromal PV) and hypercellular ET associated with megakaryocytic granulocytic myeloproliferation (EMGM). Four main molecular types of clonal MPN can be distinguished: JAK2V617F-positive ET and PV; JAK2 wild-type ET carrying the MPL515; mutations in the calreticulin (CALR) gene in JAK2/MPL wild-type ET and MF, and a small proportion of JAK2/MPL/CALR wild-type ET and MF patients. The JAK2V617F mutation load is low in heterozygous normocellular WHO-ET. The JAK2V617F mutation load in hetero-/homozygous PV and EMGM is clearly related to MPN disease burden in terms of splenomegaly, constitutional symptoms and fibrosis. The JAK2 wild-type ET carrying the MPL515 mutation is featured by clustered small and giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow (WHO-ET), and lacks features of PV. JAK2/MPL wild-type, CALR mutated hypercellular ET associated with PMGM is featured by dense clustered large immature dysmorphic megakaryocytes and bulky (cloud-like) hyperchromatic nuclei, which are never seen in WHO-ECMP-defined JAK2V617F mutated ET, EMGM and PV, and neither in JAK2 wild-type ET carrying the MPL515 mutation. Two thirds of JAK2/MPL wild-type ET and MF patients carry one of the CALR mutations as the cause of the third distinct MPN entity. WHO-ECMP criteria are recommended to diagnose, classify and stage the broad spectrum of MPN of various molecular etiologies.

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