A consortium of cancer researchers at the Children’s Medical Center Research Institute at UT Southwestern, the University of Michigan Comprehensive Cancer Center, and the University of California at San Francisco have unraveled the mystery of how leukemia-causing mutations enable pre-leukemic stem cells to outperform their healthy counterparts.
It has long been understood that the main factor in the development of leukemia is the accumulation of multiple mutations, primarily in blood-forming stem cells. Because these initial “pre-leukemic” mutations enjoy a competitive advantage on pre-leukemic stem cells, they are able to multiply and quickly outpace the development of normal stem cells, leading to the onset of the disease.
What this new investigation, which was recently published online on the Nature website, has revealed is that, ” . . . the overpowering ability of the pre-leukemic cells is tied to a very unusual bimodal mechanism — triggering one subset of stem cells to clonal expand by dividing more, and another subset to provide long-term self-renewal by dividing less,” according to a recent press release.
Sean Morrison, Ph.D., director of CRI, professor of pediatrics and the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center, explained that, “The discovery that a single mutation can have different effects on different subpopulations of stem cells adds a new layer of complexity to our understanding of the process by which leukemia arises,” adding that, “It will now be interesting to determine whether all mutations that increase stem cell competitiveness prior to the initiation of cancer do so through similar bimodal effects within the stem cell pool.”
The study revealed the new insights into the progression of pre-leukemia into the onset of the disease by engineering mice so that they would carry Nras, a tumor-causing genetic mutation that researchers believe is part of the early stages of leukemia. The press release explains that, “[i]nstead of losing their capacity to self-renew and diminishing — as would normally be the case when blood-forming stem cells divide — the pre-leukemic stem cells in the mice with Nras were observed gaining in their ability to self-renew and expanding, thus showing that the mutation had a differentiating effect on the cells.”
Dr. Kevin Shannon, M.D., professor of pediatrics at the University of California at San Francisco, where the study originated, sought to put the revelation involving Nras into context, explaining, “This finding is of particular interest for hematologists because NRAS is one of the most common genes that is mutated in pediatric and adult blood cancers,” adding, “The unique properties of hematopoietic stem cells containing NRAS mutations discovered by Dr. Morrison’s team provide a logical biological explanation for why these NRAS mutations are so prevalent in leukemia cells.”
The research study’s first author Qing Li, M.D., Ph.D., an assistant professor of hematology/oncology at the University of Michigan, whose lab completed the study, put the overall findings of the research into context for what it could practically mean for the development of new leukemia treatment modalities: “The phenomenon that a mutation promotes proliferation of some cells but at the same time keeps a small number of cells in dormancy is a particularly interesting finding. We have known for many years that the persistence of a rather dormant stem cell population is responsible for frequent leukemia relapses and treatment failure. Now identifying how Nras differentially transforms the proliferative and dormant stem cells will provide us insights in the best ways to tackle the dormant population.”
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