In:
Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3514-3514
Abstract:
Abstract 3514 Isocitrate dehydrogenase (IDH) is a metabolic enzyme that catalyzes a reaction in the tricarboxylic acid cycle. Gain of function mutations in the IDH1/2 genes have been reported in different malignancies and are observed in 15–30% of de novo AML with association to a normal karyotype and to NPM1 mutations. The exact role of IDH1/2 mutations in leukemogenesis remains to be determined. IDH mutations have not previously been studied in a cohort of therapy-related myelodysplasia (t-MDS) and therapy-related acute myeloid leukemia (t-AML). To evaluate the frequency of IDH1/2 mutations in t-MDS and t-AML, and their possible association to type of previous therapy and to other genetic abnormalities, DNA from 140 well-characterized patients with t-MDS (n=89) and t-AML (n=51) were analyzed with high-resolution melting followed by sequencing. All patients have previously been examined cytogenetically and investigated for mutations in 12 other genes: FLT3(ITD, TKD), KIT, JAK2, KRAS, NRAS, BRAF, PTPN11, RUNX1, MLL(ITD), CEBPA, NPM1, and TP53. In total, IDH mutations were detected in 12 of 140 patients (9%). 3 patients had a mutation in IDH1 and 9 patients had a mutation in IDH2 (Table 1), all mutations previously reported in de novo AML. No patients had concurrent IDH1 and IDH2 mutations. IDH mutations were not related to previous therapy with alkylating agents, topoisomerase II inhibitors or radiotherapy, but were significantly associated with other types of therapy not firmly established to be leukemogenic (p=0.004). The latency period to development of t-MDS/t-AML was not different between IDH1/2 positive (+) cases and cases with IDH (wt) (64 and 48 months, respectively, p=0.118). 4/5 cases with t-MDS and IDH+ progressed to AML compared to 27/84 t-MDS cases with IDHwt (p=0.048).Table 1:Characteristics of 12 patients with t-MDS/t-AML and mutations in IDH1/2CaseAge/sext-AML/t-MDSPrevious therapyKaryotypeOther mutationsIDH Mutation1974/FAMLAlk45,XX,-7/48,XX,der(1;7)(q10;p10),+11, +13/46,XX–IDH1 R132G2963/FAMLRT46, XXNPM1 FLT3-ITDIDH1 R132G3663/FAMLAlk46,XX,+2,+8/47,XX,der(6)t(1;6) (q?25;p21),+8N-RASIDH2 R172K4472/MMDSAlk46,XY,+1,der(1;7)(q10;p10)/46,XY–IDH2 R140Q5562/FMDS→AMLRT46, XXRUNX1IDH2 R140L7272/FMDS→AMLAlk, T II, RT46,XX,+1,der(1;7)(q10;p10)/50,XX,idem, +8,+9,14+21RUNX1IDH2 R140Q8178/MMDS→AMLAlk46,XY,der(17)t(11;17)(q13;p13),i(13) (q10)/47,idem,+der(13)t(11;13) (q13;p11)IDH2 R172K10443/FMDS→AMLAlk47,XX,+1,der(1;7)(q10;p10),+8RUNX1IDH1 R132C10944/FAMLMtx, Aza46, XXIDH2 R140Q11952/FAMLAlk, T II, RT46, XXNPM1IDH2 R140Q13325/MAMLVCR, MTX, Asp,6-MP46, XXIDH2 R140Q18060/MMDS→AMLMtx46, XXMLL-ITDIDH2 R140Q6-MP, 6 mercaptopurine; Alk, alkylating agent; Asp, l-asparaginase; Aza, azathioprine; Mtx, methotrexate; RT, radiotherapy, T II, topoisomerase inhibitor, VCR, vincristine. IDH mutations were significantly associated with a normal karyotype (6/12 cases with IDH+ vs. 18/128 with IDHwt, p=0.006) and der(1;7)(q10;p10) resulting in trisomi 1q and loss of 7q (4/12 cases with IDH+ vs. 7/128 with IDHwt, p=0.008), but was inversely correlated to other chromosome 7 abnormalities (1/12 cases with IDH+ vs. 54/128 with IDHwt, p=0.03). No patient with mutated IDH had chromosome 5 abnormalities, TP53 mutations or recurrent balanced translocations. 7/12 patients with mutated IDH1/2 had other gene mutations characteristic of AML (Table 1). The frequency of each of these other mutations were not different from patients with wildtype IDH1/2 (RUNX1, p=0.4; NPM1, p=0.2; FLT3, p=1.0; MLL, p=0.165; N-RAS, p=1.0). In conclusion, mutations of IDH1/2 were observed in 9% of patients with t-MDS/t-AML. They were not related to any specific type of therapy but perhaps associated with transformation from MDS to AML. IDH mutations clustered in the genetic pathway characterized by a normal karyotype and mutations of NPM1, and the pathway characterized by 7q−/−7 and RUNX1 point mutations. The significant association observed between IDH1/2 mutations and der(1;7)(q10;p10) may indicate that this cytogenetic aberration represents a specific entity, biologically distinct from other chromosome 7 abnormalities. This is also supported by the different clinical outcome between cases with der(1;7) and other cases with -7/7q- (Sanada et al, Leukemia 2007). Disclosures: No relevant conflicts of interest to declare.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V118.21.3514.3514
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2011
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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