Le nuove mutazioni oltre JAK2: IDH1/2 e LNK. Dr.ssa Lisa Pieri

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1 Le nuove mutazioni oltre JAK2: IDH1/2 e LNK Dr.ssa Lisa Pieri

2 First report of IDH1 muta5ons in myeloid malignancies: detected by sequencing an AML genome, preferen5ally clustering with intermediate risk AMLs Muta5ons first discovered in gliomas and secondary glioblastomas AML (16/188 mutated cases, 8%) R132C 8/16 (50%) R132H 7/16 (44%) R132S 1/188 IDH2 R172 0/188 Gliomas and secondary glioblastomas (about 80% mutated) R132C 7/161 (4%) R132H 142/161 (88%) R132S 4/161 R172 0/188 No indipendent prognos5c value with respect to overall survival in mul5variate analysis Mardis E et al, NEJM 2009; 361: Yan H et al. NEJM 2009; 360:765-9

3 NADP+-dependent isocitrate dehydrogenase genes, IDH1 and IDH2 IDH1 (Chr 2q33.3) IDH2 (Chr 15q26.19) COINVOLTI NEL CICLO DI KREBS

4 IDH1 and IDH2 mutations lead to biochemical gain of function IDH, Isocitrate dehydrogenase (IDH1 =cytoplasmic; IDH2 = mitocondrial): NADPdependent enzyme that catalyze the oxidative decarboxilation of isocitrate to α- ketoglutarate, with concomitant production of NADPH. Isocitrate NADP IDH1 IDH2 NADPH α-ketoglutarate NADPH IDH1 R132 IDH2 R172 2-hydroxyglutarate NADP Mutated proteins harbour a new enzyma5c ac5vity: produc5on and accumula5on of 2HG,a rare metabolite normally present at very low levels in healthy cells Yan H et al. NEJM 2009; 360:765-9 Gross S et al, JEM, 2010; 207:339

5 Reduc5on of NADPH and glutathione and increase of ROS Reduc5on of akg, that normally ac5vate proline hydroxylase that inac5vate HIF1a, and consequently increasing in HIF1a and its associated target Homozygous missense muta5ons have not been iden5fied: the protein is necessary to produce NADPH Abdel Wahab and Levine, JEM 2010,207 4,

6 Different mutations have the same effect IDH muta5ons R 132 (IDH1) R 140 (IDH2) R 172 (IDH2) IDH muta5ons frequency in 78 AML samples 7.7% 9% 4.4% 15.4% Ward et al, Cancer Cell 17, , March 16, 2010

7 Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms 31% of BP MPN 0% of CP MPN Acquired early during the progression to leukemia Green A, Beer P, NEJM 2010; 362:369-70

8 Gene;c analysis of leukemic transforma;on in MPNs All four possible mutational combinations were observed IDH1 muta5ons is most commonly observed in pts with JAK2, TET2, ASXL1 Abdel Wahab O, Cancer Research 2010;,70(2)

9 Tefferi et al., Leukemia (2010) 24,

10 IDH muta5ons were infrequent in chronic or fibro5c phase disease and significantly more prevalent in blast phase disease IDH co occurs with a JAK2, MPL or TET2 muta5on, and muta5onal frequency did not appear to be influenced by either the type of the coexis5ng muta5on or the presence or absence of each specific muta5on IDH mutated cases were more likely to be nullizygous for JAK2 46/1 haplotype Tefferi et al., Leukemia (2010) 24,

11 Clinical correlates and prognos0c relevance in PMF IDH mutated chronic phase PMF cases ohen belonged to a low or intermediate risk category (p=0.32) IDH mutated blast phase PMF was less likely to display complex karyotype (p 0.001) CP PMF BP PMF BP MPN

12 Novel muta+ons in the inhibitory adaptor protein LNK (SH2B3) drive JAK STAT signaling in pa+ents with myeloprolifera+ve neoplasms LNK exon 2 muta0ons (Pleckstrin homology domain): 603_607delGCGCT and 613C G: dele5on of five base pairs and a missense muta5on leading to a premature stop codon Found in 1 pt JAK2 PMF 622G C: missense muta5on yielding a subs5tu5on of glutamine for glutamic acid (E208Q) Found in 1 pt JAK2 ET Oh ST et al, Blood Aug 12;116(6): % of 33 JAK2 MPN

13 Oh ST et al, Blood Aug 12;116(6):988 92

14 Oh ST et al, Blood Aug 12;116(6):988 92

15 ID DG JAK2V617F IDH LNK 1 2 PMF AML PMF AML VF 29% VF 30% 658>A; G220R 644C>T;A215V 139 pts: 61 postmpn AML 78 CP MPN 3 4 PMF AML PMF AML NA NA VF 22% VF NA NA IDH2 R140Q IDH2 R140Q 644C>T;A215V _delGGCCCCG, 955_delA _delGGCCCCG,955_delA 8 mutated cases (13%) 9.8% mutated in BP MPN 5 PMF AML 688C>T;A223V 700G>A; D234N 88% had PMF in CP 6 PMF AML 659G>T; G220V 7 postpmf AML VF 25% 685G>A; G229S 8 postpv AML VF 80% 624G>A; E208E 6 missense muta5ons 1 synonymous muta5on 2 dele5ons (same case) Muta5onal hot spot No clear genotype phenotype correla5on All in PH domain or just distal to PH domain Pardanani et al. Leukemia Oct;24(10):

16 LNK Mutations in JAK2 Mutation Negative Erythrocytosis 8 pts with: Erythrocytosis low erythropoie5n levels absence of JAK2, MPL, EPOR muta5ons 2 mutated pts: 622G T: nonsense muta5on resul5ng in the subs5tu5on of a stop codon for glutamic acid (E208X), with trunca5on of PH and SH2 domain. 644C T: missense muta5on resul5ng in the subs5tu5on of valine for alanine A215V), absent in lymphocytes. Conserva5ve aminoacid change. Also found in JAK2V617F nega5ve BP PMF. LNK muta;ons are part of the missing link in the pathogenesis of JAK2 muta;on nega;ve idiopathic erythrocytosis or polycythemia vera. Lasho TL et al, N Engl J Med Sep 16;363(12):

17 Dr.ssa ElisabGa Antonioli Dr. Niccolò Bartalucci Dr.ssa Flavia Biamonte Dr.ssa Costanza Bogani Dr.ssa Paola Guglielmelli Dr.ssa Tiziana Fanelli Dr.ssa Elisa Malevol0 Dr.ssa Serena Mar0nelli Dr. Alessandro Pancrazzi Dr.ssa Chiara Paoli Dr.ssa Ambra Spolverini Dr. Lorenzo Tozzi Thanks to: Prof. Alessandro Vannucchi