title: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Dean
authors.initials: D
authors.lastname: Margeson
authors.forename: Kelsi B
authors.initials: KB
authors.lastname: Holland
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000032:analysis; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D010641:Phenotype; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D035683:MicroRNAs; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human