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The 1st World Congress on Controversies in Hematology (COHEM)
Rome Sept 2-5, 2010
NO Alessandro M. Vannucchi University of Florence, Section of - - PowerPoint PPT Presentation
NO Alessandro M. Vannucchi University of Florence, Section of - - PowerPoint PPT Presentation
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
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Essential Thrombocythemia Polycythemia Vera Primary Myelofibrosis
“MOLECULAR” mimicry in the classical MPD
“Three disorders, or the same disorder?”
JAK2V617F
50-60% 50-60% >95%
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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)
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JAK2V617F is sufficient to induce a MPN
PV MF
Zaleska, Plos One 2006
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JAK2V617F level determines disease phenotype
wt V617F wt V617F VavCre; FF1 ET-like disease
- NO erythrocytosis
- thrombocytosis
- moderate neutrophilia
wt V617F MxCre; FF1 Transgenic mice Retroviral transduction PV-like disease
- erythrocytosis
- thrombocytosis
- neutrophilia
PV-like disease
- erythrocytosis
- NO thrombocytosis
- neutrophilia
Tiedt R, Blood 2008
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JAK2V617F level determines disease severity
KI mouse with JAK2V617F under endogenous JAK2 promoter control
- Heterozygous mice has features of PV
- Significantly greater leukocytosis,
reticulocytosis, thrombocytosis
- Marked expansion of erythroid progenitors
and EPO-independent colonies
- Larger spleen size
- Bone marrow fibrosis
homozygosity
Akada H, Blood 2010
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JAK2 V617F allele burden in MPN
20 40 60 80 100
JAK2 V617F allele burden (%) PV ET PMF PPV/ET MF
Adapted from Antonioli et al. Haematologica 2008; 93:41 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
UPD at 9p24
PV ET
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A “continuum” between JAK2V617Fpos ET and PV
Campbell P, Lancet 2006
JAK2V617F pos ET resembles PV:
- increased erythropoiesis
lower ferritin lower MCV lower sEPO
- higher leukocyte count
- more venous thromboses
- more frequent PV “transformation”
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A “continuum” between JAK2V617Fpos ET and PV
Carobbio A, Exp Hematol 2009
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- 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
JAK2 V617F allele burden and disease progression
Silver RT, 2010; Passamonti F, 2010
PV PV
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Two routes to leukemia in JAK2V617Fpos MPN
JAK2 mutation
Normal HSC unknown mutation Founder clone ET VF PV MF VF VF AMLVF AMLWT
Beer P, Blood 2010
7/7* 1/9* *, P< .001
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Passamonti F, Haematologica 2009
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
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JAK2V617F AND MPN
A mechanistic model ...
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sex & age allele burden hereditary
predisposition
disease duration iron
- ther
mutations
……….
PV
PMF
ET
genetic instability
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