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Jan 25, 2023 •201 likes •377 views

The 1 st World Congress on Controversies in Hematology (COHEM) Rome Sept 2-5, 2010 MPNs MYELOPROLIFERATIVE NEOPLASMS Are JAK2 positive PV, ET and IM different diseases ? NO Alessandro M. Vannucchi University of Florence, Section of

  1. The 1 st World Congress on Controversies in Hematology (COHEM) Rome Sept 2-5, 2010 MPNs – MYELOPROLIFERATIVE NEOPLASMS Are JAK2 positive PV, ET and IM different diseases ? NO Alessandro M. Vannucchi University of Florence, Section of Hematology

  2. “PHENOTYPIC” mimicry in the classical MPN Primary Myelofibrosis Essential Thrombocythemia Polycythemia Vera “Three disorders, or manifestations of one same disorder ?”

  3. “MOLECULAR” mimicry in the classical MPD Primary 50-60% Myelofibrosis JAK2 V617F 50-60% >95% Essential Thrombocythemia Polycythemia Vera “Three disorders, or the same disorder ?”

  4. Animal models -I • Retroviral models (Wernig, Blood 2006; Lacout, Blood 2006; Bumm, Cancer Res 2006; Zaleska, Plos One 2006) • Transgenic models (Tiedt, Blood 2008; Xing, Blood 2008; Shide, Leukemia 2007) • Knock-in models – Constitutive (Marty, Blood 2010) – Conditional (Mullally, Cancer Cell 2010; Akada, Blood 2010; Li, Blood 2010)

  5. JAK2V617F is sufficient to induce a MPN PV MF Zaleska, Plos One 2006

  6. JAK2V617F level determines disease phenotype Retroviral transduction Transgenic mice VavCre; FF1 MxCre ; FF1 wt wt wt V617F V617F V617F ET-like disease PV-like disease PV-like disease • NO erythrocytosis • erythrocytosis • erythrocytosis • thrombocytosis • thrombocytosis • NO thrombocytosis • moderate neutrophilia • neutrophilia • neutrophilia Tiedt R, Blood 2008

  7. JAK2V617F level determines disease severity KI mouse with JAK2V617F under endogenous JAK2 promoter control • Heterozygous mice has features of PV homozygosity • Significantly greater leukocytosis, reticulocytosis, thrombocytosis • Marked expansion of erythroid progenitors and EPO-independent colonies • Larger spleen size • Bone marrow fibrosis Akada H, Blood 2010

  8. JAK2 V617F allele burden in MPN PV UPD at 9p24 ET V617F allele burden (%) 100 80 60 40 20 JAK2 0 PPV/ET PV ET PMF Adapted from Antonioli et al. Haematologica 2008; 93:41 MF Scott et al. Blood. 2006; 108:2435 Dupont et al. Blood 2007; 110:1013 Kralovics et al. Exp Hematol 2002; 30:209 Kralovics et al. NEJM 2005; 352:1779

  9. A “ continuum ” between JAK2V617F pos ET and PV JAK2V617F pos ET resembles PV: - increased erythropoiesis lower ferritin lower MCV lower sEPO - higher leukocyte count - more venous thromboses - more frequent PV “ transformation ” Campbell P, Lancet 2006

  10. A “ continuum ” between JAK2V617F pos ET and PV Carobbio A, Exp Hematol 2009

  11. JAK2 V617F allele burden and disease progression • Transformation to MF was more frequent among homo PV (23% vs 2% in hetero; P< .009 Tefferi A, Cancer 2006 ; and, 11.5% vs 1.4%, P< .001 Vannucchi A, Blood 2007 ) and in homo ET (14.3%) vs hetero (4.7%) vs WT (1.6%; P < .01) Vannucchi A, Blood 2007 PV PV Silver RT, 2010; Passamonti F, 2010

  12. Two routes to leukemia in JAK2V617F pos MPN JAK2 unknown mutation mutation Normal Founder ET VF VF VF PV MF HSC clone 7/7* AMLVF 1/9* *, P< .001 AMLWT Beer P, Blood 2010

  13. Genetic predisposition and JAK2V617F gene-dosage effect in a patient with familial ET who progressed to PV and PPV-MF * at the time of PV Passamonti F, Haematologica 2009

  14. JAK2V617F AND MPN A mechanistic model ...

  15. other mutations allele burden hereditary predisposition genetic instability disease duration iron sex & age ……… . PV ET PMF

  16. …and the winner is… . PMF

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