Combined Mutations of FLT3, IDH1,IDH2, JAK2, NPM1,c-KITgenes in Chinese Patients with Myelodysplastic Syndromes

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, JAK2^V617F, NPM1, FLT3-ITD,c-KIT genes mutations in MDS and analyzed the interaction with other mutations in Chinese patients with MDS.

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 JAK2^V617F 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.

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 JAK2^V617F revealed the presence of NPM1 exon 12 (2.27% 2/88) and JAK2^V617F(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 (P<0.001),lower WBC count(P<0.05).whereas, there were no differences in sex, platelet count for IDH mutation vs wildtype. In detail,both two patients with NPM1 mutation presented normal karyotype at the age of 61 and 58 years, and blast count of bone marrow was 11% and 10%, respectively,none progressed to AML after 7 months of follow-up. JAK2^V617F mutations were observed exclusively in the RAEB category and old years(>60years),but mutation status that is or not potentially useful for predicting progression to AML need further studying.

FIDH2 mutations are frequent in Chinese patients with de vono MDS, and associated with older age, lower WBC count at diagnosis.JAK2^V617F 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.

No relevant conflicts of interest to declare.