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Researchers unravel mystery of how leukemia-causing mutations enable pre-leukemic stem cells to outperform their healthy counterparts

ANN ARBOR, Mich. – Researchers at the Children’s Medical Center Research Institute at UT Southwestern, the University of California at San Francisco and the University of Michigan Comprehensive Cancer Center have solved a mystery that has stumped scientists for years, discovering how leukemia-causing mutations enable pre-leukemic stem cells to outperform their healthy counterparts. 

The development of leukemia is known to depend upon the accumulation of multiple mutations, mainly in blood-forming stem cells. Scientists have surmised that the initial “pre-leukemic” mutations confer a competitive advantage on pre-leukemic stem cells, allowing them to expand in number and crowd out normal stem cells. 

The investigation, published online today in Nature, discovered that the overpowering ability of the pre-leukemic cells is tied to a very unusual bimodal mechanism — triggering one subset of stem cells to clonally expand by dividing more, and another subset to provide long-term self-renewal by dividing less.

“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,” said Sean Morrison, Ph.D., director of CRI, professor of pediatrics and the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center. “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 involved engineering mice to carry a tumor-causing genetic mutation known as Nras believed to be involved in the early stages of leukemia development. Instead 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.

“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,” said Dr. Kevin Shannon, M.D., professor of pediatrics at the University of California at San Francisco, where the study originated. “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 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.” said study first author Qing Li, M.D., Ph.D., assistant professor of hematology/oncology at the University of Michigan, whose lab completed the study. “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.” 

The study began when Li was a hematology/oncology fellow in Shannon’s lab, continued when Li worked in the same capacity in Morrison’s previous lab at U-M, and was completed in Li’s own lab at U-M. 

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