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Molecular Mutation Status Identifies Prognostically Significant Risk Groups in AML

Posted on January 31 2012

Pathology Top Pick

Cytogenetic characteristics are the most important prognostic features in AML; however, roughly half of AMLs are cytogenetically normal (CN AML). Beyond conventional karyotyping, AMLs might be further prognostically stratified by molecular analysis targeted to genes that include but are not limited to FLT3, C-KIT, N-RAS, NPM1, CEBPA, WT1, ASXL1, DNMT3A, MLL, IDH1, IDH2, and TET2. Unfavorable molecular features are known to include MLL mutation or FLT3 internal tandem duplications (ID) in the presence of wild-type NPM1 in CN AMLs and C-KIT mutation in core-binding factor mutated AMLs, those with t(8;21) or inv(16).

Yang Shen et al. Blood (2011) 118:5593 evaluate the prevalence, prognostic significance, and association of numerous molecular genetic abnormalities with established recurrent cytogenetic changes in a large series (1185) of acute myeloid leukemias (AML) that were subdivided into three sets: (group I); 158 with t(8;21) and 18 with inv(16) (group II); and 387 with t(15;17) (group III).

In group I AMLs, 75% had at least one mutation with relative frequencies: CEBPA 22.0%, NPM1 20.9%, MLL 14.0%, TET2 12.7%, DNMT3A 12.3%, FLT3 10.8%, IDH1 9.3%, IDH2 9.8%, C-KIT 5.4%, N-RAS 5.9%, ASXL1 5.2%, WT1 3.7%. Group II AMLs most frequently contained mutations of C-KIT (25.6%) and N-RAS (9.7%), and group III AMLs most frequently contained FLT3 (13.4%) and N-RAS (5.4%). DNMT3A mutations appeared to predict poor outcome in the few cytogenetically "favorable" AMLs that were DNMT3A+. By multivariate analysis of group I AMLs, mutation status of DNMT3A, MLL, NPM1, and CEBPA genes was prognostically significant independent of cytogenetics and produced three risk groups: (1) Favorable risk; biallelic CEBPA mutations or NPM1-mutated/ wild-type DNMT3A; (2) Intermediate risk: all others; (3) Poor risk; DNMT3A-mutated or MLL (11q23) rearranged.

It seems that among cytogenetically normal acute myeloid leukemias, molecular mutation status of four genes, DNMT3A, MLL, NPM1, and CEBPA, identifies prognostically significant risk groups. In addition to diagnostic and prognostic significance, this large body of work further illuminates the molecular biology of AML, which is likely to contribute to evolving drug development and disease monitoring strategies.

Yang Shen et al. (2011) Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia Blood. 118(20):5593-5603

Editorial. Guy E.Nichols MD, PhD