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Loss Of Enzyme Stymies Differentiation Of Blood-Forming Cells

December 7, 2011

In the bone marrow, blood-forming (hematopoietic) stem cells become one of the myriad kinds of blood cells in the body or they can self-renew, maintaining that pool.

However, the lack or mutation of a gene for an enzyme called Dnmt3a (DNA methyltransferase 3a) results in an abundance of stem cells and a lack of blood cells, said a consortium of researchers led by those at in the Stem Cells and Regenerative Medicine Center at Baylor College of Medicine in a report online in the journal Nature Genetics.

Implication for acute myeloid leukemia

The finding could have implications for some people with a cancer called acute myeloid leukemia, said Dr. Margaret Goodell, professor of pediatric–hematology and oncology and director of the center. A recent report in the New England Journal of Medicine found that many patients with the disorder also have a mutation in the gene.

“The mice with the abundance of stem cells seem to function all right and they do not have leukemia,” said Dr. Grant Challen, an instructor in the Center for Cell and Gene Therapy at BCM, Texas Children’s Hospital and The Methodist Hospital. However, he and Goodell hypothesize that a second event could be required to cause the cancerous change. Mice may not live long enough to suffer the second event. Most humans with the disease are over the age of 60, they said.

When a stem cell gets a signal telling it to differentiate, it needs certain genes to remain in the stem cell state. Before it can differentiate, Dnmt3a must target those genes for methylation. (In methylation, a methyl molecule added to the gene prevents it from being transcribed into RNA that provides the template for making a protein. This inactivates the gene.) If the cell lacks functional Dnmt3a, it will have a harder time overcoming the barriers to differentiation.

“It is fascinating that you have this basic science mechanism of DNA methylation in which you change the gene molecularly and now you also have this fascinating clinical link that is important biologically,” said Goodell, who is also a member of the Center for Cell and Gene Therapy.

Possible target for therapeutics

Goodell said the gene might be involved in a disease called myelodysplastic syndrome, which is characterized by an abundance of stem-like cells in the bone marrow. Patients with this disorder have anemia (a lack of red blood cells) and a deficient immune system. Ten percent of patients with that disease also have a mutation in the Dnmt3a gene.

This basic science finding in mice may explain some of what happens in acute myeloid leukemia and myelodysplastic syndrome and may provide a target for therapeutics in the future.

Others who took part in this research include Deqiang Sun, Mira Jeong, Min Luo, Yuanxin Xi, Gretchen J Darlington, all of BCM; Jaroslav Jelinek, Yue Lu, Hongcang Gu, Shoudan Liang and Jean-Pierre J. Issa of The University of Texas MD Anderson Cancer Center in Houston; Jonathan S Berg of the University of North Carolina in Chapel Hill; Christoph Bock and Alexander Meissner of the Broad Institute in Cambridge, Mass.; Aparna Vasanthakumar and Lucy A. Godley of the University of Chicago,

Funding for this work came from the National Institutes of Health, the American Society of Hematology, the Ellison Foundation, the American Heart Association, the Cancer Prevention and Research Institute of Texas and the Functional Genomics Core.

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