Understanding the molecular basis of acute myeloid leukemias: where are we now?

Abstract

Although the treatment modalities for acute myeloid leukemia (AML) have not changed much over the past 40 years, distinct progress has been made in deciphering the basic biology underlying the pathogenesis of this group of hematological disorders. Studies show that AML development is a multicause, multistep and multipathway process. Accordingly, AMLs constitute a heterogeneous group of diseases. The thorough understanding of the molecular basis of AML is paving the way for better therapeutic approaches. Multiple novel drugs are being introduced and new, more efficient and less toxic formulations of conventional therapeutics are becoming available. Here, we review the recent advances in the comprehension of the molecular processes that lead to the onset of AML and its translation into clinical practice.

Keywords: AML; leukemogenesis; molecular oncology.

Figure 1.. Acute myeloid leukemia pathogenesis: acute myeloid leukemia development is a multicause, multistep and multipathway process.

AML: Acute myeloid leukemia.

Figure 2.. The molecular consequences of common acute myeloid leukemia mutations.

Mutations in myeloid transcription factor (TF) and TF fusions caused by chromosomal rearrangements such as translocations lead to transcriptional deregulation and impaired hematopoietic differentiation (top left). Mutations in tumor suppressor genes influence the transcription and checkpoint responses of the cell (top center). Mutations in signaling genes (e.g., FLT3 receptor) confer a proliferative advantage through the RAF/MEK/ERK, JAK/STAT and PI3K/AKT/NFKB signaling axes (top right). DNMT3A, IDH1/2 and TET2 mutations acting through the 2-hydroxyglutarate oncometabolite production deregulate DNA methylation (top middle). Mutations in genes responsible for the cellular epigenetic regulation (e.g., ASXL1 and EZH2) lead to alterations in chromatin modification (H3 and H2A histone methylation on K79, K27 and K119 lysine residues, respectively), while MLL/AF9 fusion gene through aberrant methylation upregulate HOX gene expression and thus expands stem cells and blocks differentiation (bottom middle). Mutations of NPM1 gene, encoding a multifunctional shuttling protein, result in the formation of cytoplasmic mutant of NPM1 known as NPMc+ and cause delocalization of NPM1-interacting proteins, influence ribosome biogenesis and TP53 stability (bottom right). Mutations in spliceosome complex genes (SRSF2, SF3B1 and U2AF1) are involved in deregulated RNA processing including intron retention (bottom center). Cohesin complex gene mutations, in other words, SMC1A, SMC3, STAG2 and RAD21, trigger increased chromatin accessibility and enhanced binding of AML1 and GATA2 TFs enforcing stem cell programs (bottom left).