Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

“…However, research in defining prognostic factors has recently moved to an examination of molecular markers. 17,18 Molecular profiling develop models offering improvements in risk stratification and design novel approaches to treat patients more effectively. Molecular markers are particularly important in patients displaying a normal karyotype.…”

The role of HOXB2 and HOXB3 in acute myeloid leukemia

“…Therefore, the self-renewal ability of those cells is increased, and regulation of normal cell proliferation is disturbed. The major genetic changes include mutation in genes affecting cell proliferation (FLT3, KIT, NRAS/KRAS, JAK/STAT and PTPN11), myeloid differentiation (RUNX1/AML1 and CEBPA), cell cycle regulation or apoptosis (TP53, NPM1), and up-regulation of genes involved in stem-cell maintenance (HOXA, HOXB) [1][2][3][4].…”

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

“…During the last 15 years, major advances have been made in the understanding of CN-AML pathogenesis by the discovery of many genetic abnormalities affecting cell proliferation, differentiation, apoptosis or cell cycle regulation. These abnormalities include many gene mutations (NPM1 (nucleophosmin), FLT3 (fms-like tyrosine kinase receptor-3), CEBPA, MLL, N-RAS, RUNX1 (Runtrelated transcription factor 1), WT1 (Wilms tumor 1) and so on), 1 deregulation of gene expression (EVI1 (Ecotropic Viral Integration Site 1), BAALC (brain and acute leukemia, cytoplasmic), MN1 (meningioma 1), ERG (Ets-related gene), WT1 and so on), 2 --8 as well as acquired copy number variations and regions with loss of heterozygosity. 9,10 Prognostic significance within CN-AML has been well established for FLT3 internal tandem duplication (FLT3-ITD), NPM1 and CEBPA mutations.…”