Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic neoplasm which results in clonal proliferation of abnormally differentiated hematopoietic cells. In this review, mechanisms contributing to myeloid leukemogenesis are summarized, highlighting aberrations of epigenetics, transcription factors, signal transduction, cell cycling, and the bone marrow microenvironment. The mechanisms contributing to AML are detailed to spotlight recent findings that convey clinical impact. The applications of current and prospective therapeutic targets are accentuated in addition to reviews of treatment paradigms stratified for each characteristic molecular lesion - with a focus on exploring novel treatment approaches and combinations to improve outcomes in AML.

Keywords: Acute myeloid leukemia; Cell cycle; Epigenetics; Leukemogenesis; Novel strategies; Oncoprotein; Signal transduction; Targeted therapy; Transcription factor.

Fig. 1.

Epigenetic regulators in acute myeloid leukemia. A. The DNMT family converts cytosine residues to 5-methylcytosine and are responsible for somatic methylation patterns. DNMT^mut creates aberrant methylation patterns and disruption of gene expression. Hypo-methylating agents, including azacitidine and decitabine, restore methylation through inhibition of DNMT^mut, allowing for increased tumor suppressor gene expression. B. TET2 modifies 5-methylcytosine to 5-hydroxymethylcytosine, resulting in DNA demethylation. TET2 is inhibited by 2-hydroxyglutarate (2HG), produced by mutated IDH1 or IDH2. IDH1 and IDH2 inhibitors indirectly restore methylation patterns and result in myeloid differentiation C. ASXL1 cooperates with BAP1 to deubiquitinate lysine 119 on histone H2, contributing to a gain-of-function effect and resulting in a differentiation block. Depletion of BAP1 restores HOX gene expression by decreasing HOX-mediated replicative immortality.

Fig. 2.

Pro-survival proteins and apoptosis in acute myeloid leukemia. MCL-1 and BCL-2 are pro-survival proteins that are frequently targeted or dysregulated in AML. Venetoclax is a BCL-2 inhibitor that results in apoptosis through mitochondrial cytochrome C release. BCL-2 resistance can occur through up-regulation of MCL-1, which can be overcome through suppression of the RAS pathway by p53.

Fig. 3.

Signaling pathways in acute myeloid leukemia. Stem cell factor (SCF) binds to the KIT tyrosine kinase receptor, triggering activation of downstream RAS and PI3K. Similarly, the FLT3 ligand (FLT3-L) binds to the FLT3 tyrosine kinase receptor and activates RAS and PI3K. RAS cascades into MEK and ERK, resulting in cell proliferation. PI3K activates AKT, which leads to mTOR-driven cell growth. AKT also inhibits FOXO and other pro-apoptotic proteins, leading to cell survival.