Study alleviates precancerous “clonal outgrowth” in blood cells

A common, spontaneous mutation in blood stem cells, which has been linked to a higher risk of blood cancer and cardiovascular disease, may promote these diseases by altering the stem cells’ gene activity programming and the mix of blood cells they produce, according to a study co-led by researchers from the Dana-Farber Cancer Institute, Weill Cornell Medicine, New York-Presbyterian and the New York Genome Center.

The blood stem cell mutation, known as DNMT3A R882, leads to the growth of a large population, or “clonal outgrowth,” of circulating blood cells that also contain this mutation. In general, such mutant outgrowths become more common with age, and are thought to represent a very early, premalignant stage of cancer development. However, the molecular details of how they arise are difficult to pin down, because the mutant cells look and function much the same as normal cells. In the study, which appears in Nature Genetics, the researchers took on this challenge to shed light on the effects of R882 mutations in DNMT3A, the most mutated gene in blood cells.

The study was a collaboration between the lab of Irene Ghobrial, MD, director of the Clinical Investigator Research Program at the Dana-Farber Cancer Institute, and the lab of Dan Landau, MD, PhD, associate professor of medicine in the Department of Hematology and Medical Oncology , at Weill Cornell Medicine. The Ghobrial Lab provided samples of blood stem cells from the marrow of patients in remission from multiple myeloma patients where they found clonal outgrowths of blood cells are relatively common.

“These findings help us understand how these mutated cells outgrow normal cells and pave the way for potential future interventions that target these cells to prevent cancers and other clonal outgrowth-related disorders,” the study authors said. “Our hope is that by uncovering molecular signatures like these, we will be able to target these clonal outgrowths and prevent the development of cancer in people who are still healthy.”

Researchers evaluated more than 6,000 cells from the patients, using “single-cell multi-omics” techniques to detect the DNMT3A R882 mutation, as well as map gene activity and chemical markers on DNA called methylations. that turn off nearby genes. In this way, they captured in unprecedented detail how the mutation-containing blood stem cells differed from their normal counterparts.

For example, the researchers found that the production of mature blood cells by the mutant stem cells was skewed toward red blood cells and the cells that make blood-clotting platelets — providing possible reasons for the higher risk of cardiovascular disease in patients with clonal outgrowths in their veins. blood.

The DNMT3A gene normally codes for an enzyme called methyltransferase that helps place methylations on DNA. The researchers found that the mutation’s disruption of normal methylation led to a lack of these “off switches” in the genome and the abnormal activation of key genes. The latter include inflammation-directing genes and cancer-associated growth genes — all consistent with a growth and survival benefit for the mutated cells and a higher risk of their progression to cancer.

The researchers plan to further investigate clonal outgrowths resulting from other mutations. They are also developing their multi-omics techniques to increase the speed and scale of these studies.

*This press release is adapted from a press release from Weill Cornell Medicine.

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