Search

Abstract 4647 Introduction: Myelodysplastic syndromes (MDSs) comprise a heterogeneous group of stem cell disorders characterized by ineffective hematopoiesis presenting with peripheral cytopenias together with hyperplastic bone marrow.Patients with MDS show an increased but variable risk of progression to acute myeloid leukemia (AML).Although, cytogenetic abnormalities are known as a major role in pathogenetic mechanisms, only 30% to 50% of patients with de novo MDS have abnormal karyotype,An further understanding of the molecular pathogenesis of MDS is needed, however,littleis known about the genetic events and their potential value for predicting progression to AML. We aimed at studying the potential significance of IDH1,IDH2, JAK2V617F, NPM1, FLT3-ITD,c-KIT genes mutations in MDS and analyzed the interaction with other mutations in Chinese patients with MDS. Methods: We examined Chinese patients with de novo MDS for mutations in the IDH1,IDH2, JAK2, NPM1, FLT3-ITD,C-KIT genes.Female/male ratio was 39/49 and age ranged from 28.0–79.0 years (median, 58.0years).Genomic DNA was extracted from diagnostic marrow specimens,FLT3 internaltandem duplication(FLT3 –ITD) and JAK2V617F mutation was screened using polymerase chain reaction (PCR),c-KIT, NPM1 and IDH genes were assessed by PCR followed by direct sequencing, according to previously described protocols. Results: F Overall, in 7 patients (7.95%) IDH mutations were detected. None of them had IDH1 mutation,6 missense mutations (6.8%) in IDH2 (R140Q n=6) and 1 synonymous substitution (c.519G>A) in IDH2. Molecular genetic analysis of NPM1 and JAK2V617F revealed the presence of NPM1 exon 12 (2.27% 2/88) and JAK2V617F(3.4% 3/88 ) mutations. FLT3-ITD,c-KIT mutations in exon 8 and 17 were not detected at MDS stage and concurrent mutations were not found. 4 of 6 cases with IDH2 missense mutations presented normal karyotype. IDH2 mutations were restricted to 3 morphologic categories:refractory cytopenia with multilineage dysplasia (RCMD n=2),refractory anemia with excess blasts (RAEB-2 n=3) and refractory anemia with ringed sideroblasts(RARS n=1), Patients with IDH2 mutations were older (P60years),but mutation status that is or not potentially useful for predicting progression to AML need further studying. Conclusions: F IDH2 mutations are frequent in Chinese patients with de vono MDS, and associated with older age, lower WBC count at diagnosis.JAK2V617F and NPM1 mutations are rare in MDS,but both of them correlated with morphologic categories.IDH1,c-KIT,FLT3-ITD were detected in our cohort,suggesting that these mutations may be not a key role in pathogenetic mechanisms of MDS. Disclosures: No relevant conflicts of interest to declare.

Abstract 4638 Introduction: Acute myeloid leukemia (AML) is a heterogeneous group of aggressive disease with complex process,gene mutations play an important role in AML pathogenesis. Several genes have been identified in AML,such as FLT3, c-KIT, NPM1 and JAK2. Indeed, some mutations have revealed prognosis subgroups and modified the therapeutic management of these leukemias. Recently,novel mutations in IDH1(amino acid R132)and IDH2 (R140 and R172)have been found in patients with AMLs,but the frequency and impact on biological and prognostic features in Chinese patients with AMLs remain unknown. We aimed at studying the potential significance of IDH1 and IDH2 mutations in AML and analyzed their interaction with other mutations in Chinese patients with de novo AMLs. Methods: We searched 163 Chinese patients with de novo AML for mutations in the IDH1,IDH2, JAK2, NPM1, FLT3-ITD,C-KIT genes.Female/male ratio was 98/65 and age ranged from 17.0–74.0years (median, 41.0years).Genomic DNA was extracted from diagnostic marrow specimens,FLT3 internaltandem duplication(FLT3 –ITD) and JAK2V617F mutations were screened using polymerase chain reaction (PCR),c-KIT, NPM1 and IDH genes were assessed by PCR followed by direct sequencing, according to previously described protocols. Results: Overall, IDH mutations were found in 25 patients (15.3%) —IDH1 in 7 patients (4.29%) and IDH2 in 18 patients (11.04%). A total of 4 types of IDH1 mutations were identified(c.395G>A, p.R132H,n=4 Gc.394C>A, p.R132S,n=1 Gc.394C>G, p.R132G,n=1 Gc.315C>T, n=1),six out of the seven patients with the missense mutations and the overall frequency of missense mutations in IDH1 was 3.68% (6/163). Both synonymous substitution (c.315C>T; rs11554137) in IDH1 and IDH2R140 mutation occurred in one patient. No mutated cases had both IDH1 and IDH2 missense mutations, suggesting that the mutations are mutually exclusive. IDH2 mutations caused changes of R140 (c.419G>A,p.R140Q,n=18), R172 mutation was not found in our study. The NPM1 mutation in exon 12 was present in 18.35% (n=29 29/158), 25 cases had FLT3-ITD(15.8% 25/158),One case had frame insertion/deletions of c-KIT in exon 8,7 cases had the substitution of a single amino acid in exon 17(4.57%,7/153),none of them had JAK2V617F mutation. IDH- mutated cases showed a higher frequency of concurrent NPM1 mutation compared with wildtype cases (48.3% 14/29 vs 10.8% 11/129), IDH mutations were also more frequent in FLT3-ITD mutation vs FLT3-ITD wildtype (44.0% 11/25 vs 10.5%14/133).10 patients had both FLT3-ITD and NPM1 mutations, concurrent mutations in NPM1, FLT-ITD were detected in 5 cases with the IDH mutation. None of all cases had both IDH and C-KIT mutations. IDH mutations were more often in cytogenetically normal AML cases(20.5% 15/73 vs5.8% 3/52. Patients with IDH mutations were older (51:40 P=0.003), whereas, there were no differences in sex,WBC and platelet count for IDHmut and IDHwt. Conclusion: Our results show that IDH mutations, especially IDHR140 were frequent genetic alterations in Chinese patients with de novo AMLs, and associated with older age, normal karyotype at diagnosis.There was strong association of IDH mutations with NPM1 and FLT3-ITD mutations, suggesting that IDH mutations may act cooperatively in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.