Research led by the University of Michigan has identified a gene critical to controlling the body’s ability to create blood cells and immune cells from blood-forming stem cells, known as hematopoietic stem cells. The data findings provide new insights into the underlying mechanics of how the body creates and maintains a healthy blood supply and immune system, both in normal conditions and in situations of stress, like the body experiences following a bone marrow transplant. The opensource study is published in the Journal of Clinical Investigation.
Along with helping scientists better understand the body’s basic processes, the current study opens new lines of inquiry about the Ash1l gene’s potential role in cancers known to involve other members of the same gene family, like leukemia, or those where Ash1l might be highly expressed or mutated.
The team explain that it’s vital to understand how the basic, underlying mechanisms function in a healthy individual if the medical community want to try to develop interventions for when things go wrong, adding that leukemia is a cancer of the body’s blood-forming tissues, so it’s an obvious place that they plan to look at next. The team theorise that if they find that Ash1l plays a role, then that would open up avenues to try to block or slow down its activity pharmacologically.
Dysfunction of blood-forming stem cells is well known in illnesses like leukemia and bone marrow failure disorders, the researchers state. Blood-forming stem cells can also be destroyed by high doses of chemotherapy and radiation used to treat cancer. The replacement of these cells through bone marrow transplantation is the only widely established therapy involving stem cells in human patients. However, the team add, even in the absence of disease blood cells require constant replacement, most blood cells last anywhere from a few days to a few months depending on their type.
Over more than five years the team identified a previously unknown but fundamental role played by the Ash1l gene in regulating the maintenance and self-renewal potential of these hematopoietic stem cells. The Ash1l (Absent, small or homeotic 1-like) gene is part of a family of genes that includes MLL1 (Mixed Lineage Leukemia 1), a gene that is frequently mutated in patients who develop leukemia. The current study found that both genes contribute to blood renewal; mild defects were seen in mice missing one or the other, but lacking both led to catastrophic deficiencies. The team state that they now have clear evidence that these genes cooperate to develop a healthy blood system.
The current study found that Ash1l-deficient mice had normal numbers of hematopoietic stem cells during early development, but a lack of stem cells in maturity, an indication the cells were not able to properly maintain themselves in the bone marrow. The Ash1l-deficient stem cells were unable to establish normal blood renewal after a bone marrow transplant. Moreover, Ash1l-deficient stem cells competed poorly with normal blood-forming stem cells in the bone marrow and could easily be dislodged.
The data findings show that Ash1l regulates the expression of multiple downstream ‘homeotic’ genes, which help ensure the correct anatomical structure of a developing organism.
After the U.S. dropped atomic bombs on Hiroshima and Nagasaki, doctors noticed that radiation patients weren’t able to generate new white blood cells to fend off infections. Subsequent experiments on mice showed that bone marrow transplants from healthy animals into irradiated ones could renew their ability to make new blood cells. The technique was eventually developed for use in human patients, including those whose blood stem cells are killed off by cancer treatments. But work continues in the laboratory setting.
Using these previous studies the team surmise that by continuing to investigate the basic, underlying mechanisms which builds on a history of research in fruit flies and in mice, they are helping to untangle the complex machinery of the blood renewal that may lay the foundation for new human treatments.
Source: U-M Comprehensive Cancer Center
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