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.

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The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcription factor strongly implicated in myelopoiesis through control of proliferation and differentiation of myeloid progenitors. Recently, several works have reported the presence of CEBPA-acquired mutations in hematological malignancies. In this work, we analyzed characteristics of mutations and their correlation with disease characteristics described in previous studies. In the 1175 patients reported, 146 CEBPA mutations were identified in 96 patients. Mutations were found in the whole gene sequence, but cluster regions were clearly identified. Furthermore, two categories of mutations were reported: out-of-frame ins/del often in the N-terminal region, and in-frame ins/del often in the C-terminal region. CEBPA mutations were reported exclusively in acute myeloid leukemia (AML) (according to WHO classification criteria) and mutated patients preferentially belonged to M1, M2 and M4 FAB subtypes. All but one case belonged to the 'intermediate' prognostic subgroup of MRC classification. In the absence of poor prognostic factors, patients with CEBPA mutation had favorable outcome, very similar to that of the t(8;21), inv(16), t(15;17) subgroup. Systematic analysis of CEBPA mutations, in addition to that of alterations in master genes of hematopoiesis, may be useful to assess the prognosis of AML particularly in patients belonging to the 'intermediate' prognostic subgroup.