Current findings for recurring mutations in acute myeloid leukemia

Abstract

The development of acute myeloid leukemia (AML) is a multistep process that requires at least two genetic abnormalities for the development of the disease. The identification of genetic mutations in AML has greatly advanced our understanding of leukemogenesis. Recently, the use of novel technologies, such as massively parallel DNA sequencing or high-resolution single-nucleotide polymorphism arrays, has allowed the identification of several novel recurrent gene mutations in AML. The aim of this review is to summarize the current findings for the identification of these gene mutations (Dnmt, TET2, IDH1/2, NPM1, ASXL1, etc.), most of which are frequently found in cytogenetically normal AML. The cooperative interactions of these molecular aberrations and their interactions with class I/II mutations are presented. The prognostic and predictive significances of these aberrations are also reviewed.

Figure 1

The model of the "classical" class I and class II mutations in AML. This model comprises class I mutations that activate signal transduction pathways and confer a proliferation advantage on hematopoietic cells, and class II mutations that affect transcription factors and primarily serve to impair hematopoietic differentiation [15,16]. The development of AML is a multistep process that requires at least these two genetic abnormalities for the development of the disease. Class I mutations are shown in yellow boxes and class II mutations are in red boxes. The combination of each mutation is demonstrated as blue rings. Runx 1 mutations and MLL rearrangements may be exception in this model, as shown in orange boxes, since co-occurrence is observed between these two mutations.

Figure 2

The combination model of class I and unclassified mutations in AML. Several unclassified mutations (NPM1, WT1, Dnmt3a) co-occur with several class I mutations. These may fall into putative class II mutations (termed "class II' mutations"), shown in pink boxes. Within these mutations, co-occurrences were observed between Dnmt3a, NPM1mutations (shown in orange boxes), therefore, these mutations may be exception of this model.

Figure 3

The combination model of class II and unclassified mutations in AML. Several unclassified mutations (ASXL1, IDH1/2, TET2) co-occur with several class II mutations. These may fall into putative class I mutations (termed "class I' mutations"), shown in light yellow boxes. IDH1/2 mutations co-occurred not only with MLL rearrangement, but also Dnmt3a and NPM1 mutations, as shown in orange boxes.