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.

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

“…In pursuit of drug candidates targeting recurrent oncogenic IDH2 mutations, we initiated a high-throughput screen for inhibitors of the enzyme carrying the most prevalent IDH2 mutation in AML, IDH2 R140Q (29)(30)(31). Several triazine compounds active against the IDH2 R140Q homodimer emerged, and initial hit-to-lead chemistry led to compound 1, the first sub-100 nmol/L inhibitor of IDH2 R140Q (Fig.…”

A single-tube, sensitive multiplex method for screening of isocitrate dehydrogenase 1 (IDH1) mutations

“…1 Very recently, a series of reports about this mutation in AML have been published in a cluster of manuscripts. [1][2][3][4][5][6][7] As IDH1 mutation brings prognostic information in glioma and possibly AML, 4,[8][9] identification of IDH1 R132 mutations will bring increasing clinical relevance. Moreover, the mutation seems quite stable and may serve as a marker for monitoring minimal residual disease.…”

“…[1][2][3][4][5][6][7] Another upstream forward primer was used to generate a product as an internal control. Combination of these 7 forward primers and a common reverse primer ( Figure 1A) would generate a shorter mutant and a longer control product in any genomic DNA containing any type of R132 mutation, whereas only the longer product would be seen in samples without this mutation ( Figure 1B).…”

Making a Meal of Multiple Mutations in Acute Myeloid Malignancies

“…Tumorassociated mutations in IDH1 and IDH2 were initially found with high frequency in brain tumors, 12 and subsequently were found with lower frequency (ϳ10% of tumors) in AML. 8,9 Surprisingly, the mutations in these genes result in neomorphic enzymatic activity capable of converting ␣-ketoglutarate to R(Ϫ)-2-hydroxyglutarate (2-HG). 13 Levels of 2-HG are increased in IDH-mutant tumors and have been shown to inhibit the activity of TET2, an enzyme encoded by another gene frequently mutated in AML.…”

“…Mutations in IDH1 and IDH2 occur in defined regions of the coding sequence, 8 and Patel and sous-chefs 11 used standard PCR to amplify the regions of interest, followed by a high-resolution melting curve analysis of the duplex DNA from their PCR products. Any sample that showed a significant difference in melting curves, relative to wildtype standards, was flagged and subjected to Sanger sequencing.…”