Familiarità e suscettibilità nelle neoplasie ematologiche Sindromi mieloproliferative familiari. Elisa Rumi

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1 Familiarità e suscettibilità nelle neoplasie ematologiche Sindromi mieloproliferative familiari lisa Rumi Dipartimento di matologia Oncologia Fondazione IRS oliclinico San Matteo avia Firenze 14 marzo 2013

2 Why hereditary predisposition to MN? Several lines of evidence: henotypic diversity of MN (, V, MF) despite a common somatic mutation (JK2 V617F) xistence of biclonal MN with 2 independent clones in the same patient ommon polymorphims predisposing to MN (JK2 haplotype) Familial clustering of MN

3 Hereditary predisposition to MN 1 st line of evidence: host modifying influences JK2 V617F Mouse model Balb/c 57Bl/6 Strain specific modifiers: Balb/c mice show markedly elevated WB count, splenomegaly, fibrosis compared to 57Bl/6 mice Werning et al, Blood 2006

4 Why hereditary predisposition to MN? Several lines of evidence: henotypic diversity of MN (, V, MF) despite a common somatic mutation (V617F JK2) xistence of biclonal MN with 2 independent clones in the same patient ommon polymorphims predisposing to MN (JK2 haplotype) Familial clustering of MN

5 Hereditary predisposition to MN 2 nd line of evidence: biclonal MN he mutation-bearing clones express different alleles of the X-linked SN (rs in IDS) the 2 mutations had arisen in unrelated hematopoietic stem cells: mutation-bearing clones are clonally unrelated Beer et al, BJH 2009

6 Why hereditary predisposition to MN? Several lines of evidence: henotypic diversity of MN (, V, MF) despite a common somatic mutation (V617F JK2) xistence of biclonal MN with 2 independent clones in the same patient ommon polymorphims predisposing to MN (JK2 haplotype) Familial clustering of MN

7 What haplotype is? Set of DN sequences (one or more loci or SN) very close along the chromosome hey tend to be inherited together due to absence of recombination during crossover (genetic linkage ) h"p://hapmap.ncbi.nlm.nih.gov/originhaplotype.html.en

8 Hereditary predisposition to MN 3 rd line of evidence: JK2 haplotype predisposing to MN 88% of all JK2-V617F mutations occur on the JK2 haplotype Olcaydu et al, Nat enet /1 is a significant constitutional risk factor for development of V617F positive MNs [OR =3.7; 95% I, ] Jones et al, Nat enet 2009 Not 46/1 1 46/

9 Role of the JK2 haplotype: 2 hypotheses Hypermutability: there is a specific mutational mechanism by which V617F preferentially arises on a 46/1 haplotype Fertile ground: mutation rate on 46/1 and non-46/1 haplotypes is the same but the probability of clinically manifest disease is higher if V617F arises on 46/1 ampbell, Nat enet 2009

10 Hereditary predisposition to MN 3 rd line of evidence: JK2 haplotype predisposing to MN he JK2 haplotype predisposes: to JK2-exon 12 mutated MN to M-mutated MN to and MF independently from JK2 status he JK2 haplotype is the major common genetic susceptibility factor for MN Olcaydu et al, eukemia 2009 Jones et al, Blood 2010 ardanani et al, eukemia 2010 efferi et al, eukemia 2010

11 Why hereditary predisposition to MN? Several lines of evidence: henotypic diversity of MN (, V, MF) despite a common somatic mutation (V617F JK2) xistence of biclonal MN with 2 independent clones in the same patient ommon polymorphims predisposing to MN (JK2 haplotype) Familial clustering of MN

12 Hereditary predisposition to MN 4 th line of evidence: familial clustering of MN Familial clustering in 7.6% of apparently sporadic MN Relatives of MN patients have a 5- to 7- fold increased risk of developing MN Rumi et al, JO 2007 andgren et al, Blood 2008

13 Familial clustering of MN: pathogenesis he known recurrent MN-associated mutations (JK2, M, 2, B) are acquired as somatic mutations also in familial MN genetic predisposition to acquisition of different JK2 mutations may be inherited I:1 I:2 Olcaydu et al, Haematologica 2011 ietra et al, Blood 2008 * * * II:1 II:3 II:5 JK2 V617F-pos V V II:7 JK2 xon 12-pos 2-pos

14 Familial clustering of MN: pathogenesis frequency in % JK2 haplotype frequency control sporadic MN familial MN he haplotype frequency was higher in familial (0.44) and sporadic (0.42) MN than in control (0.27) Familial MN did not differ significantly from sporadic MN in disease risk conferred by the haplotype ( ns) Olcaydu et al, Haematologica 2011

15 Familial clustering of MN: clinical phenotype linical phenotype may be homogeneous (all relatives affected have the same MN) or mixed (different MNs in the same pedigree) llele burden varies among MNs Rumi et al, JO 2007

16 Familial clustering of MN: clinical phenotype at diagnosis ge, years Median Range Sex Male Female WB, x10 9 /l Median Range Hb, g/dl Median Range x10 9 /l Median Range Familial V (n=36) Sporadic V (n=188) Familial (n=24) Sporadic (n=157) Familial MF (n=15) Sporadic MF (n=78) Splenomegaly, No. (%) 7 (19) 47 (25) (8) 3 (2) (60) 48 (62) 0.1 hrombosis, No. (%) 10 (28) 44 (23) (8) 23 (14) (20) 12 (15) 0.7 Hemorrhage, No. (%) 1 (3) 15 (8) (4) 5 (3) (6) Familial MN similar to sporadic MN Rumi et al, JO 2007

17 Familial clustering of MN: complications high JK2 V617F allele burden is correlated with evolution to myelofibrosis in familial V (p<0.0001) and has a trend in familial (p=0.09) Malak et al, Blood ell Mol and Dis 2012

18 Familial clustering of MN: overall survival 100%; V 83%; MF 56% V 83% 83% V 37% 57% Rumi et al, JO 2007 Malak et al, Blood ell Mol and Dis 2012

19 Familial clustering of MN: differential diagnosis Hereditary thrombocytosis/ erythrocytosis Familial MN 1. olyclonal hematopoiesis 2. Mendelian inheritance 3. M, HO, OR mutations are disease causing genes 1. lonal hematopoiesis 2. omplex inheritance 3. JK2 mutations are secondary genetic events po receptor O2 sensing O2 affinity HO M rythrocytosis hrombocytosis ssential thrombocythemia olycythemia vera rimary myelofibrosis

20 Hereditary rythrocytosis Inheritance po Mechanism rimitive rythrocytosis F D ow runcated po Rec Secondary rythrocytosis O 2 sensing pathway defects: VH mutation R High VH mutation HD2 mutation HIF2α mutation D D Inapp high High HD2 mutation HIF2α mutation Hb with altered O 2 affinity: Hb variants with high affinity 2,3-D deficiency D D-R High High lobin chain mutations nzymatic defects

21 po Hereditary rythrocytosis: F (rimary familial and congenital polycythemia) 16 different mutations diverse affecting por cause truncation of the po receptor S por JK2 JK2 S S SH1 he inhibitory control is lost; continuous activation of JK2 and S S S Nucleus Kralovics et al. N ngl J Med 2005; 352: ; James et al. Nature 2005; 434:1144-8; Baxter et al. ancet 2005; 365: ; evine et al. ancer ell 2005; 7:387-97

22 Hereditary rythrocytosis : F (rimary familial and congenital polycythemia) High hemoglobin ow serum po bsence of splenomegaly Headache, dizziness Rare thromboses bsence of leukemic evolution utosomal dominant inheritance

23 Hereditary rythrocytosis Inheritance po Mechanism rimitive rythrocytosis F D ow runcated po Rec Secondary rythrocytosis O 2 sensing pathway defects: VH mutation R High VH mutation HD2 mutation HIF2α mutation D D Inapp high High HD2 mutation HIF2α mutation Hb with altered O 2 affinity: Hb variants with high affinity 2,3-D deficiency D D-R High High lobin chain mutations nzymatic defects

24 Hereditary rythrocytosis : O 2 sensing pathway defects (VH, HD, HIFα mutations) Normoxia Hypoxia rg200rp Ub ly537rp VH HIFα O O 2 HIFα 2 HIFα HD Formation of the HIFα-VH complex HD hydroxilates HIFα ro317rg HIFα HIFα HIFα HIFα Intracitoplsmic accumulation of HIFα and nuclear translocation Nucleus VH Ub HIFα proteasomal degradation Degradation of HIFα is impaired; continuous transcription of O po HIFα HR HIFβ Increased transcription of po gene in the kidney

25 Hereditary rythrocytosis: O 2 sensing pathway defects (VH, HD, HIFα mutations) ndemic in huvash Republic and Ischia; frequency of the 598 allele: - huvashia: Ischia: Worldwide Haplotype of Ischia patients=haplotype of huvash cluster single-founder hypothesis utosomal recessive inheritance (VH), utosomal dominant inheritance (HD, HIFα) High hemoglobin, po normal-high Young age, early mortality due to cerebral vascular events and peripheral thrombosis

26 huvash olycythemia: case report 36 yr, Hb 25 g/dl, splenomegaly Normal 50, po 115 mu/ml JK2 V617F and exon 12 neg Bone marrow biopsy not consistent with V Reference MN R W R200W Reference -y R200W R W avia unpublished data

27 ? M13_20 (..) Reference -y R MN W/R W/R VH R200 M12_570 (D..) Reference -y R MN W VH R200 R MN -y W M12_569 (D..) Reference R R MN -y R M12_568 (D.N.) Reference VH R200 W/R W/R VH R200 M13_21 (I..) Reference -y R MN R avia unpublished data -y VH R200 MN R R M13_22 (I.R.) Reference W/R W/R VH R200

28 Hereditary rythrocytosis Inheritance po Mechanism rimitive rythrocytosis F D ow runcated po Rec Secondary rythrocytosis O 2 sensing pathway defects: VH mutation R High VH mutation HD2 mutation HIF2α mutation D D Inapp high High HD2 mutation HIF2α mutation Hb with altered O 2 affinity: Hb variants with high affinity 2,3-D deficiency D D-R High High lobin chain mutations nzymatic defects ercy et al, JH 2009

29 Hereditary rythrocytosis : High affinity of Hb for O 2 (High-oxigen-affinity haemoglobinopathy, 2,3 D deficiency ) Hypoxia Dissociation curve shifts left less oxigen delivery to tissues High-oxigen-affinity Hb 2,3 D deficiency HIFα HIFα HIFα HIFα HIFα O 2 ytoplasmic accumulation of HIFα and nuclear translocation Nucleus Decreased delivery of oxigen to tissues; continuous transcription of O HIFα HR HIFβ Increased transcription of po in the kidney po

30 Hereditary rythrocytosis: altered affinity of Hb for O 2 (High-oxigen-affinity haemoglobinopathy, 2,3 D deficiency) 50 : partial pressure of O 2 at which 50% of Hb is saturated with oxigen (26 mmhg). High affinity hemoglobin and 2,3 D deficiency shift the curve leftward, thus reducing 50 Hb High affinity Hb 2,3 D deficiency

31 High affinity hemoglobin: case report 55 yr, Hb 17.7 g/dl mmhg (reduced) JK2 V617F and exon 12 neg Hb San Diego Rumi et al, JIM 2008

32 Hereditary thrombocytosis O HO M S505N S M JK2 JK2 S S Rare utosomal dominant inheritance: family history HO or M mutations S S Nucleus

33 Familial MN: JK2 germline mutations / / / Recent observation of new germline JK2 mutations: V617I, R564Q, H608N Mead et al, NJM 2012 theridge et al, SH 2011 Rumi et al, H 2012

34 onclusions Harutyunyan et al, Hematol Oncol lin North m. 2012

35 cknowledgements Department of Hematology Oncology Fondazione IRS oliclinico S. Matteo Università di avia Mario azzola manuela Boveri Ilaria asetti ristiana ascutto Daniela ietra enter for Molecular Medicine (emm) Vienna Robert Kralovics shot Harutyunyan Jelena Milosevic na uda Division of Hematology zienda ospedaliera universitaria Fondazione Macchi Varese Francesco assamonti