Genetic Alterations and Their Clinical Implications in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a hematologic malignancy with great variability in the pathogenesis, clinical features, and treatment outcomes. Advances in molecular research have greatly improved our understanding of the leukemogenesis in AML. A two-hit model proposes that the development of AML requires the cooperation between at least two classes of gene mutations.(Frohling, et al 2005, Gilliland 2002) Class I mutations, such as RAS, FLT3, KIT, PTPN11 and JAK2 mutations, involve genes in the kinase signaling pathways leading to cell survival and proliferation and Class II mutations, such as t(15;17)/PML-RARA, inv(16)/CBFB-MYH11 and t(8;21)/RUNX1-RUNX1T1 fusions, and MLL/PTD, and CEBPA and AML1/RUNX1 mutations, involve transcription factors or cofactors resulting in impaired hematopoietic differentiation. In addition to genetic abnormalities, increasing evidences show that epigenetic deregulations are also critical to the pathogenesis of AML.(Chen, et al 2010) Compatible with these findings, several novel mutations involving genes related to epigenetic modifications, such as isocitrate dehydrogenase 1 (IDH1), IDH2, ten-eleven translocation 2 (TET2), additional sex comb-like 1 (ASXL1), and DNA methyltransferase 3A (DNMT3A) were detected in AML recently.(Chou, et al 2010b, Delhommeau, et al 2009, Gelsi-Boyer, et al 2009, Ley, et al 2010, Mardis, et al 2009, Metzeler, et al 2011) Risk-adapted treatment may not only improve the prognosis, but also reduce the toxicity from the therapy in patients with AML. In addition to the conventional risk factors, such as age, white blood cell (WBC) counts and cytogenetics, molecular genetic alterations, such as mutations of NPM1, CEBPA, AML1/RUNX1, WT1, FLT3, TET2, and DNMT3A etc., are also important prognostic factors in AML patients. Furthermore, the gene mutations which are stable during treatment courses can also be used as biomarkers to monitor minimal residual disease (MRD). Herein, we will review the gene mutations in AML and discuss their clinical implications.