Molecular Mutations and Their Cooccurrences in Cytogenetically Normal Acute Myeloid Leukemia

Abstract

Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making. The recent advances in clinical genomics have led to the recategorization of CN-AML into favorable or unfavorable subgroups. The relapsing nature of AML is thought to be due to clonal heterogeneity that includes founder or driver mutations present in the leukemic stem cell population. In this article, we summarize the clinical outcomes of relevant molecular mutations and their cooccurrences in CN-AML, including NPM1, FLT3^ITD, DNMT3A, NRAS, TET2, RUNX1, MLL^PTD, ASXL1, BCOR, PHF6, CEBPA^biallelic, IDH1, IDH2^R140, and IDH2^R170, with an emphasis on their relevance to the leukemic stem cell compartment. We have reviewed the available literature and TCGA AML databases (2013) to highlight the potential role of stem cell regulating factor mutations on outcome within newly defined AML molecular subgroups.

Figure 1

Kaplan-Meier curves for disease-free survival according to the presence or absence of the specific gene alterations. Gene alterations include mutations, deletions, fusions, and gene amplifications. All the alterations for IDH1 are mutations. Over 95% of the alterations are mutations for DNMT3A, TET2, and FLT3. The rest of the alterations are multiple alterations for DNMT3A and TET2 and deletions for FLT3. Database used for analysis is TCGA, NEJM 2013 [94]. The cBio Cancer Genomics Portal was used for the analysis [95] (http://cbioportal.org).