Study highlights cancerous ‘clonal growth’ in blood cells – ScienceDaily

The common spontaneous mutation in blood stem cells, which has been linked to an increased risk of leukemia and cardiovascular disease, may promote these diseases by altering stem cells’ programming for gene activity and the mixture of blood cells that produce them, according to study co-authors at Weill Medicine. Cornell, New York Presbyterian, New York Genome Center, Harvard Medical School, and Dana-Farber Cancer Institute.

Blood stem cell mutation, known as DNMT3A R882And the It leads to the growth of a large population, or “clonal growth” of circulating blood cells that also contains this mutation. In general, these mutant outgrowths become increasingly common with age, and are thought to represent a very early stage of cancer development. However, it has been difficult to determine the molecular details of how they appeared, because mutant cells broadly look and function like normal cells. In the study appearing on September 22 nature genetics The researchers overcame this challenge to shed light on the effects of R882 mutations in DNMT3Athe gene most mutated in blood cells.

“These findings help us understand how these mutant cells outperform normal cells, and pave the way for potential future interventions that target these cells to prevent cancers and other conditions associated with clonal cell growth,” said study senior author Dr. Dan Landau, assistant professor of medicine. in the Department of Hematology and Medical Oncology, Associate Professor of Physiology and Biophysics and a member of the Sandra and Edward Mayer Cancer Center at Weill Cornell Medicine, a principal faculty member of the New York Genome Center and an oncologist at New York-Presbyterian/Weill Cornell Medical Center.

The study was a collaboration between Dr. Landau’s lab and the lab of Dr. Irene Gabriel, associate professor of medicine at Harvard Medical School and the Dana-Farber Cancer Institute. Dr. Gabriel’s team provided blood stem cell samples from the marrow of patients in remission from multiple myeloma – patients who have found clonal outgrowths of blood cells to be relatively common.

Dr. Landau’s team evaluated more than 6,000 cells from patients, using ‘single-cell multicellular’ techniques to discover DNMT3A R882 . mutationAnd the And to map gene activity and chemical marks on DNA called methylations, programming marks that turn off nearby genes. In this way, they recorded in unprecedented detail how the mutant blood stem cells differed from their normal counterparts.

The researchers found, for example, that mutant stem cell production of mature blood cells was skewed toward red blood cells and cells that make clotted platelets—providing potential rationales for higher cardiovascular risk in patients with clonal metabolites. in their blood.

gene DNMT3A It usually encodes an enzyme called methyltransferase, which helps put methylation onto DNA. The researchers found that disruption of the mutation in normal methylation led to a deficiency of these “stop switches” across the genome and abnormal activation of key genes. The latter included proinflammatory and cancer-related growth genes—all of which concur with the growth and survival advantage of mutant cells, and their increased risk of progression to cancer.

Anna Nam, MD, associate professor of pathology and laboratory medicine in the Department of Pathology and Laboratory Medicine and a member of the Mayer Cancer Center at Weill Cornell Medicine, is a pathologist at New York Presbyterian/Weill Cornell Medical Center.

The researchers plan to conduct further studies on the clonal products from other mutations. They are also developing their own multi-omics techniques to increase the speed and scale of these studies.

“We should soon be able to do studies of many cells simultaneously, giving us a more complete picture of what’s going on,” said co-first author Neville Dusaj, a three-institutions PhD student at Landau. laboratory.

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