IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

Abstract

PURPOSE To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. Results IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication-negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. CONCLUSION IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.

Fig 1.

Impact of distinct IDH mutation types on clinical outcome of patients with cytogenetically normal acute myeloid leukemia. (A) Disease-free survival and (B) overall survival of younger molecular low-risk patients according to IDH1 mutation status. (C) Complete remission rates according to R172 IDH2 mutation status. ITD, internal tandem duplication; wt, wild-type; CR, complete remission.

Fig 2.

Genome-wide gene- and microRNA-expression profiles associated with R172 IDH2 mutations. (A) Gene-expression and (B) microRNA-expression signatures, derived from comparing older patients with R172 IDH2 mutations and those with the wild-type IDH1/IDH2 genes. Rows represent gene probe sets (A) or microRNA probes (B), and columns represent patients. Patients are grouped by IDH2 mutational status (R172 or wild-type). Expression values of the probe sets and microRNA probes are represented by color: green indicates expression less than the median value and red indicates expression greater than the median value for the given gene probe set or microRNA probe.