IDH1Mutation In Chinese Acute Non-lymphoblastic Leukemia Patients And Its Association With Other Oncogene Mutations

Acute non-lymphoblastic leukemia (ANLL) is a malignant hematologic disordercharacterized by abnormal expansion of differentiation-defective myeloid cells.Pretreatment cytogenetic analysis of ANLL blasts is essential to form prognosticsubgroups in order to adopt risk-adapted treatment. Nevertheless,40–45%of ANLLpatients lack such cytogenetic markers. Recently, molecular genetic alterations havebeen reported to improve the prognostic stratification of cytogeneticnormal-ANLL(CN-ANLL) patients. Isocitrate dehydrogenase1(IDH1) metabolic genesencode cytosolic enzymes that catalyze the conversion of isocitrate toα-ketoglutarate(α-KG). Acquired somatic mutations of IDH1have recently beenreported in ANLL cases ranging from2%to14%. Molecular analyses reveal that IDH1mutation interrupts the normal ability of enzyme to bind substrates and subsequentacquisition of novel enzymatic activity. IDH1mutation result in the loss of normalcatalytic activity, the production of α-KG, and gain of a new activity, the production ofan oncometabolite,2-hydroxylglutarate (2-HG). The accumulation of elevated2HGincreases global DNA methylation and histone methylation and interrupts ofhematopoietic differentiation. Now, there is few reports on the clinical features ofIDH1-mutated acute myeloid leukemia in Chinese adult patients349newly diagnosed ANLL patients were analyzed for the presence of IDH1mutation by PCR followed by direct DNA sequencing. Clinical and biologicalcharacteristics were analyzed systematically.The IDH1mutation occurs in35(10%) of these349patients， and a new type ofIDH1mutations R100producing2-HG was found in this study. The IDH1mutationswere associated with FLT3-ITD(20%vs2.2%; P<0.01), CEBPA mutation(8.6%vs0.6%;P<0.01), WT1overexpression(62.9%vs2.5%; P<0.01), MN1overexpression(22.9%vs1.2%; P<0.01), PRAME overexpression(11.4%vs3.1%P<0.05). IDH1mutation wasmostly detected in ANLL-M1(5/14;35.72%), however the IDH1mutations had noimpact on overall survival(OS).In conclusion, these datas show that IDH1mutations which is common in newlydiagnosed ANLL patients are often detected in M1and accompanied by another gene aberrations, including FLT3-ITD, CEBPA mutation, WT1overexpression, PRAMEoverexpression, MN1overexpression, but the clinical impact of IDH1mutations onpatients’overall survivalcould not be observed.