Uncovering the genetic mechanism driving acute myeloid leukemia

Researchers have begun to uncover the genetic mechanisms by which acute myeloid leukemia cells with a DNMT3A mutation stay as undifferentiated cells, rather than developing into healthy mature hematocytes. The finding is the result of a new study published in Cancer Cell, and carried out by Gang Greg Wang and colleges from the University of North Carolina Lineberger (NC, USA).

Through the development of the first laboratory model of acute myeloid leukemia (AML), the team studied somatic mutations in the DNA methyltransferase 3A gene (DNMT3A), which are found in approximately 20–30% of AML cases. Using this mouse model, they demonstrated that mutations in DNMT3A promote acute leukemogenicity in the presence of mutant NRAS, induce DNA hypomethylation of key stemness genes and potentiate stemness gene expression.

Wang spoke of the importance of this research: “Due to a large-scale cancer sequencing project, the DNMT3A gene is now appreciated to be one of the top three most frequently mutated genes in human AML, and yet the role of its mutation in the disease has remained far from clear. Our findings not only provide a deeper understanding of how this prevalent mutation contributes to the development of AML, but it also offers useful information on how to develop new strategies to treat AML patients.”

He added: “In AML, the expression of these stemness genes are aberrantly maintained at a higher level. As a result, cells ‘forget’ to proceed to normal differentiation and maturation, generating immature precursor blood cells, and a prelude to full-blown cancer.”

The group also demonstrated that AML carrying DNMT3A mutations is sensitive to DOT1L inhibitors, which are currently under clinical evaluation. This discovery may pave the way for a personalized treatment strategy for AML individuals carrying the DNMT3A mutation.

Sources: Lu R, Wang P, Wang GG et al. Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development J. C. Cell DOI: 10.1016/j.ccell.2016.05.008 (2016);  University of North Carolina Lineberger press release