Gene Mutations in Acute Myeloid Leukemia — Incidence, Prognostic Influence, and Association with Other Molecular Markers

Acute myeloid leukemia (AML) is a clonal disorder affecting pluripotent stem cells and is characterized by ineffective hematopoiesis. Most AML patients harbor cytogenetic and molecular defects that identify entities with peculiar biologic and clinical data and distinct therapeutic responses. Approximately 50%–60% of de novo AML and 80%–95% of secondary AML patients display chromosomal aberrations. Structural chromosomal rearrangements are the most common cytogenetic abnor‐ malities in de novo AML, with an incidence of 40%. Last years, large collaborative studies have demonstrated the importance of cytogenetic aberrations for the prognosis of AML patients. The large group of patients with cytogenetically normal (CN) AML refers to the intermediate risk category. It is known that this group of patients is very heterogene‐ ous with respect to prognosis. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatments that are based on individual mutation profiles. Genes recurrently mutated in AML belong to distinct functional groups or pathways. A few recurring gene mutations with prognostic relevance in AML have been identified and have become incorporated into current prognostication models. For patients with CN AML, prognosis can be specified by mutational status of the genes NPM1, FLT3, and CEBPA. CN AML patients with NPM1 mutation, but no FLT3-ITD, or with CEBPA mutation, have a favorable prognosis. In contrast, CN AML patients with FLT3-ITD mutation have a poor prognosis. © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Recently a new class of mutations affecting genes for DNA methylation and posttranslational histone modification was identified in AML. These mutations frequently occur in the DNA nucleotide methyltransferase 3A gene (DNMT3A) and isocitrate dehydrogenase 1/2 gene (IDH1/2). Different studies have shown a negative impact of DNMT3A mutations on outcomes in patients with AML. The prognostic effect is known to depend on certain biological factors as well as a combination of cytogenetics and other mutations such as those in FLT3 and NPM1. In contrast, the impact of IDH1/2 mutations on prognosis is not completely understood. It appears that prognosis may depend on specific patient populations and a combination with NPM1 mutations. Moreover, a growing number of recurrent mutations in additional genes have recently been identified. Increasing evidence suggests that AML develops throughout the process of branching evolution.