Abstract
Simple SummaryAcute myeloid leukemia is a genetically heterogeneous disease and shows variable treatment outcomes. Genetic profiling has revealed different driver mutations in AML patients. Therefore, it is important to understand the biological impact of these mutations in leukemia transformation. In this review, we discuss the individual and synergistic effects of these mutations in the pathogenesis of leukemia based on the available evidence from mouse models.Acute myeloid leukemia is a clinically and biologically heterogeneous blood cancer with variable prognosis and response to conventional therapies. Comprehensive sequencing enabled the discovery of recurrent mutations and chromosomal aberrations in AML. Mouse models are essential to study the biological function of these genes and to identify relevant drug targets. This comprehensive review describes the evidence currently available from mouse models for the leukemogenic function of mutations in seven functional gene groups: cell signaling genes, epigenetic modifier genes, nucleophosmin 1 (NPM1), transcription factors, tumor suppressors, spliceosome genes, and cohesin complex genes. Additionally, we provide a synergy map of frequently cooperating mutations in AML development and correlate prognosis of these mutations with leukemogenicity in mouse models to better understand the co-dependence of mutations in AML.
Highlights
Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of leukemic stem cells and results in cytopenia in peripheral blood [1,2]
Deep sequencing enabled the discovery of driver mutations in primary and relapsed AML patients [4]
These major driver genes can be clustered into 7 functional groups: cell signaling genes, epigenetic modifier genes, nucleophosmin 1 (NPM1), transcription factors, tumor suppressors, spliceosome genes, and cohesin genes [5]
Summary
Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of leukemic stem cells and results in cytopenia in peripheral blood [1,2]. Another study has demonstrated that NRASG12D causes CMML and AML-like disease in mice [44] They have used the MSCV promoter to express the NRAS oncogene, the major discrepancy in the results may be due to the use of a different strain of mice and a high titer of the virus. NrasG12D/+ alone or p53−/− alone, cooperation of these mutations induces quiescence in megakaryocyte-erythroid progenitors (MEPs) that is sufficient to drive AML development in mice (Table 2; Supplementary Figure S3) [127]. Collaboration of Nf1 inactivation and the KRASG12D mutation induces AML in mice (Table 2; Supplementary Figure S3) [125] It is unclear whether the synergy is due to hyperactivated RAS signaling or activation of a non-RAS pathway by Nf1 deficiency. The above-mentioned mouse models of Nf1 suggest that the Nf1 mutation is a loss of function mutation and can induce AML in collaboration with other mutations
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