Meccanismi molecolari di progressione di mala0a nelle neoplasie mieloprolifera2ve croniche PAOLA GUGLIELMELLI

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1 Meccanismi molecolari di progressione di mala0a nelle neoplasie mieloprolifera2ve croniche PAOLA GUGLIELMELLI Sez. di Ematologia Università di Firenze

2 Leukemic Transforma2on in MPN MPN subtype Essen2al Thrombocythemia Polycythemia Vera Primary Myelofibrosis Incidence ader 10yrs 2-5% 5-10% 8-20% All FAB subtypes of AML have been described (ALL excepconal) EvoluCon to AML usually, but not obligatory, through transicon to PPV- /PET- MF Dismal prognosis (OS < 3-6 months) BePer survival reported for AML developed in ET pacents compared with PV or PMF Bjorkholm M, JCO 2011

3 Risk of Leukemia Transforma2on in MPN MPN Subtype Essen2al Thrombocythemia Polycythemia Vera Primary Myelofibrosis Overall Risk of AML Transforma2on (95%CI) 24.7 ( ) 33.0 ( ) 63.8 ( ) Bjorkholm M, JCO 2011

4 Generic Risk Factors for Leukemia Transforma2on in MPN Risk Factors Clinical Age Anemia RBC- transfusion dependence Thrombocythopenia Thrombocythosis Leukocytosis Peripheral blast cells Prior thrombosis Weight loss Cytotoxic drugs Biological Gene2c CirculaCng CD34 + cells ( 300/µl) Original diagnosis (consider ET vs pre- fibrocc MF) JAK2V617F allele burden in PMF Unfavorable Karyotype [monosomal karyotype, Chr17 abnormalices, Inv3/I(17q)] Specific gene mutacons Barbui T, JCO 2011; Passamon2 F, Haematologica 2008 ; Tefferi A, Eur J Haema2ol 2008; Gangat N, BJH 2007; Kiladjian JJ, Semin Thromb Hemost 2006; Finazzi G, Blood 2005; Passamon2 F Am J Med 2004;Barosi G, Blood 2001;Morel P, Blood 2010; Passamon2 F, BJH 2010; Tefferi A, BJH 2001

5 IWG- MRT Dynamic Model Predicts Progression to Leukemia in PMF The risk of progression to blast phase is 7.8- fold (Int- 2) or fold (High) higher compared with Low/Int- 1 category Passamon2 F, Blood 2010

6 Modelling Disease Progression in MPN Acquired soma2c muta2on Addi2onal n muta2on(s) GeneCc PredisposiCon Genomic Instability Genomic AberraCons / MutaCons / LOH

7 JAK2 V617F Mito2c Recombina2on and Disease progression onset of MPD heterozygous JAK2V617F mitocc recombinacon homozygous JAK2V617F myelo- fibrosis AML

8 JAK2 V617F allele burden and disease progression TransformaCon to MF was more frequent among homo PV (11.5% vs 1.4%, P<.001 ) and homo ET (14.3% vs hetero (4.7%) vs WT (1.6%; P <.01) PET- MF: V617F allele burden : 57% versus 27% in ET pts PPV- MF: V617F burden : 72% versus 52% in PV pacents Vannucchi AM, Blood 2007; Guglielmelli P Haematologica 2011; Passamon2 F, Leukemia 2010

9 Karyotypic Abnormali2es during Chronic Phase MPN 50 gains 76 delecons 147 UPD (0.1 Mbp to Mbp) Klampfl T, Blood 2011

10 Karyotypic Abnormali2es are not Correlated with Diagnosis or JAK2 Status 408 MPN pts 72.8% 62.5% Klampfl T, Blood 2011; 118:

11 Disease Progression is Associated with Accumula2on of Chromosomal Aberra2ons Chronic Accelerated Leukemic Klampfl T, Blood 2011; 118:

12 Karyotype- Dependent Risk Model in Myelofibrosis Int. (N=1) Low (N=0) High (N= 2) Very high- risk cytogene2cs [Monosomal; inv(3)/i(17q)] PB Blasts >2% Platelets <50x10 9 /L Category 3- year Leukemia HR (95% CI) LOW 3% 2.6 ( ) INT. 10% HIGH 35% 9.4 ( ) Tefferi A, Leukemia 2012

13 Cytogene2c Aberra2on in Leukemia post- MPN/MDS CUX1 IKFZ1 EZH2 ETV6 AEBP2 SOCS2 CUX2 TP53 SUZ12 Puda A, Am J Hematol 2011

14 The Muta2onal Profile of Secondary and de- novo Leukemias Milosevic JD, Am J Hematol 2012

15 The Muta2onal Profile of post- MPN and post- MDS Leukemia is Similar Milosevic JD, Am J Hematol 2012

16 Molecular Markers Commonly Associated with post- MPN Leukemia Chronic Accelerated Leukemic phase TP53 CBL IDH1/2 DelChr7 Del5q Chr1q+?? NMP1 FLT3 Pardanani et al, Leukemia 2010; Tefferi et al, Leukemia 2011; Patel et al, NEJM 2012

17 Involvement of TP53 at Leukemia Strongly Affects Survival Monoallelic TP53 mutacons in 3.1% during chronic phase TP53 mutacons or 1q gains in 45.5% of post- MPN AML Harutyunyan A et al. N Engl J Med 2011;364: Courtesy, R. Kralovics 2012, MPN Florence Mee2ng

18 Mechanisms Involved in Genomic Instability in MPN (1) INHIBITION OF NHE- 1 EXPRESSION AND BCL- XL DEAMIDATION APOPTOSIS JAK2 V617F (2) (3) DEREGULATION OF DNA DOUBLE STRAND BREAKS REPAIR HOMOLOGOUS RECOMBINATION DNA REPAIR (4) HISTONE PHOSPHORYLATION (Y41H3) EXPRESSION of ONCOGENES (LMO2) (1) Zhao et al., NEJM, 2008; (2) Plo et al. Blood. 2008; (3) Siebolds et al. Int J Cancer. 2009(4) Dawson et al., Nature, 2009

19 JAK2 V617F - induced ROS Mediate JAK2 V617F dependent Gene2c Instability in MPN cells P JAK2 V617F JAK2 617F P P Y Y P P P Y Y Y Y P P ROS Induces a growth advantage to the JAK2V617F clone nucleus Oxidative DNA damages Double-strand breaks Homologous recombination Genetic Instability Acquisition of other abnormalities Homozygous JAK2 V617F Kinase activity Disease progression

20 Models of Leukemic Transforma2on in MPN JAK2 VF JAK2 VF TP53 Del7q FLT3, NMP1, NRAS JAK2V617F pos AML JAK2V617F neg de- novo like AML

21 Complexity of Muta2onal Profile at Diagnosis A N= pts (6.4%) had >3mutaCons

22 Complexity of Muta2onal Profile at Diagnosis A N=483 Does it have predic2ve value for leukemia? «Pre- des2na2on theory» 31 pts (6.4%) had >3mutaCons

23 No Impact of JAK2 V617F on Leukemia Risk P=0.839 HR: 1.05 (95% CI, ) WT V617F (CompeCCve risk analysis)

24 MPL Muta2on Does not Affect LFS Mayo Clinic cohort Florence cohort MPL+ WT JAK2 V617F MPL+ JAK2 V617F WT Pardanani et al, Leukemia 2011.

25 EZH2 Muta2on At Diagnosis Associates with Shorter LFS P =.028 Mutated WT Leukemia (n=) 7 (31.8%) 57 (17.6%) Mut WT LFS (mo) 25.7 (18-153) 63.6 (1-328) PRC2 member genes are frequently homozygously or heterozygously deleted (JARID2 and AEBP2) or mutated (SUZ12) in post- MPN AML Guglielmelli P, Blood 2011;; Puda A, Am J Hematol 2012

26 ASXL1 At Diagnosis Associates with Higher Risk of Leukemia P< HR= 2.8 (95%CI, ) Mut WT (CompeCCve risk analysis)

27 Risk of Leukemia in ASXL1 Mutated Subjects According to IPSS Score IPSS LOW- INT1 IPSS INT2- HIGH Mut Mut WT WT P=0.009 P=0.001 (CompeCCve risk analysis)

28 SRSF2 Muta2on Inversely Correlated with LFS in Primary Myelofibrosis P= HR 1.9, 95%CI Reported in 18.9% of AML transformed from MPNs Lasho T, Blood 2012; Zang SJ Blood 2012

29 IDH1 and IDH2 Muta2ons At Diagnosis Associate with Higher Risk of Leukemia IDH mut (n=11) P< HR: 2.66, 95% CI: IDH wt (n=509) LFS: 46 vs 245 mo (P<0.0001)

30 DNMT3A, CBL and TP53 Muta2on At Diagnosis do not Predict for Leukemia in PMF DNMT3A CBL P=0.566 P=0.07 TP53 mutacons idencfied at diagnosis did not predict for leukemia in PMF (only 4 of 44 pts evolved to leukemia were TP53 mut) Guglielmelli P, ESH 2012

31 The A3669G Polymorhism of Glucocor2coid Receptor Contributes to Blast Transforma2on in PMF The A3669G allele is a suscepcbility allele for PMF (HR ) The G/G allele associated with a «more- myeloproliferacve» phenotype OS* BT- FS* 0.47 per 100 pt- yr N=21 N= per 100 pt- yr 77.6mo vs 298mo; P=0.049 *, restricted to JAK2V617F pos pts, n= mo vs 261mo; P=0.018 remained significant in mul2variate Barosi G et al, Blood 2012

32 A XPD Polymorphism Predisposes to Leukemia in Polycythemia Vera and Essen2al Thrombocythemia A Gln/Gln genotype in the XPD codon 751 found in 64 incident cases of leukemia arer ET/ PV Associated with leukemic transformacon (OR: 4.9; 95% CI: ) Hernández- Boluda et al. Blood. 2012

33 No Impact of XPD haplotype on Leukemia in PMF HR: 1.22 (95%CI, ) CC AA + AC P=0.548

34 Modelling Disease Progression in MPN Acquired soma2c muta2on Addi2onal n muta2on(s) Disease progression in MPN has strong genecc component and may be largely predetermined since the very beginning The challenge will be to assess whether «predeterminacon» is amenable to treatment (target drugs signal inhibitors, HDACi, SCT,.?)

35 Acknowledgments SecOon of Hematology, University of Florence Alessandro Vannucchi Flavia Biamonte Carmela Mannarelli Tiziana Fanelli Ambra Spolverini Maria Chiara Susini Giada Rotunno Alessandro Pancrazzi Lisa Pieri Alberto Bosi Contributors Mario Cazzola - Pavia Gianni Barosi - Pavia Francisco Cervantes - Barcelona Andrea Reiter - Mannheim Andrew Duncombe - Southampton Katerine Zoe - Athens Nick Cross - Salisbury