Faulty Genetic Instructions Drive Deadly Leukemia in Adults

Acute myeloid leukemia is one of the most common acute leukemia or blood cancer types in adults, and involves over-production of immature blood cells that then crowd out normal, healthy cells.

It is estimated there are nearly 20,000 new cases diagnosed and more than 10,000 deaths in the USA each year and studies have found that just close to 23% of people with the disease live five years once diagnosed.


Scientists at the Lineberger Comprehensive Cancer Center (Chapel Hill, NC, USA) and their colleagues have discovered how a set of faulty genetic instructions keep blood stem cells from maturing, a finding that further explains the development of acute myeloid leukemia (AML). They reveal how a mutation in the gene DNMT3A, which has been found in approximately 20% to 30% of cases of AML, gives normal cells faulty genetic instructions that contribute to the development of cancerous cells.

They also found that while the DNMT3A mutation is required for acute leukemia development, the mutation itself is not sufficient to cause cancer alone. Instead, they found that the mutation cooperates with another genetic defect in a gene called rat sarcoma (RAS) to drive cancer. They found AML cells with the DNMT3A mutation were sensitive to specific drug inhibitors of DOT1-Like Histone H3K79 Methyltransferase (DOT1L), a cellular enzyme involved in modulation of gene expression activities. As DOT1L inhibitors are currently under clinical evaluation, this translational finding suggests a potential personalized strategy for treating the human AML carrying DNMT3A mutation.

Rui Lu, PhD, the lead author of the study, said, “We found the RAS mutation stimulates these immature blood cells to be hyper-proliferate, however, these cells cannot maintain their stem cell properties, while the DNMT3A mutation itself does not have hyper-proliferative effects, but does promote stemness properties and generates leukemia stem/initiating cells together with the RAS mutation.” The study was published on June 23, 2016, in the journal Cancer Cell.

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Lineberger Comprehensive Cancer Center