Ravi Majeti, MD, PhD
Researchers at the Stanford Institute discovered that a fundamental mutation in some cancers preserves certain stem cell qualities that should be lost, and also stops cancer cells from becoming more specialized. The finding brings scientists slightly closer to understanding how cancers develop, and perhaps how to treat them, the researchers say. The research was published Oct 22, 2015 in the journal Cell Stem Cell.
The research was supported by the California Institute of Regenerative Medicine, the New York Stem Cell Foundation, the Stinehart-Reed Foundation, the Ludwig Center for Stem Cell Research and Medicine, and the National Institutes of Health (Grants R01CA188055 and P50-HG007735).
Stem cells are the only cells in the body that can reproduce themselves as well as produce cells that are slightly more specialized in function. The stem cell theory of cancer proposes that all cancers contain a number of cancer stem cells that can reproduce themselves and keep the cancer going. Without this pool of stem cells to replenish the population of cancer cells, a cancer would die out.
Normally, DNA is packed tightly with specialized proteins in a structure called chromatin. This keeps the volume of the massive DNA molecules small, but it also blocks gene expression because genes packed away in chromatin can’t be read by the cell’s protein-making machinery. When genes need to be expressed as proteins, the chromatin is unpacked in particular spots to make the genes accessible.
Oct. 22, 2015
“About 10% – 15% of cases of acute myeloid leukemia and other myeloid cancers have cohesin mutations, but no one knew what role those mutations play,” says Majeti. “What we did in this study was introduce these cohesin mutations into normal blood stem cells” and determined how this affected them.
By Christopher Vaughan
“What we are seeing is that cohesin initiates changes in DNA structure that both make cells act more like a stem cells and also make them more likely to expand the cell population, two hallmarks of cancer cell growth,” Majeti says.
At the same time, these cohesin mutants initiated changes that made it harder for cells to differentiate into more specialized cells. As cells become more specialized, they often become less able to multiply.
To look at which areas of chromatin were opened up, Majeti collaborated with Stanford researcher Howard Chang, MD, PhD, who recently developed an advanced technique to measure just that. “Overall, the cohesin mutants reduced chromatin accessibility, but if you looked at the specific places the chromatin was opened up, it was in areas important to regulating the blood stem cell,” Majeti says. Such changes may make it more likely that the cancer cells can act like stem cells, reproducing themselves to fire up the cancer.
Researchers in the laboratory of institute researcher Ravi Majeti, MD, PhD, built upon other studies that some cancers had mutations in a protein complex called cohesin, which was known mostly for engaging with chromosomes during cell division.
Majeti and his team, led by graduate student Claire Mazumdar, discovered that when cohesin mutations are inserted into normal blood stem cells, the slightly more specialized (or “differentiated”) offspring of those stem cells keep certain stem cell qualities that they should have lost. Majeti and his colleagues determined that this was happening because the altered cohesin was holding some segments of DNA in a position that made certain genes more active.