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3.24.2015

Sylvester Leader’s Genetic Studies Provide New Insights into Bone Marrow Disorders

Two important genetic studies driven by the leader of the University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center provide new insights into an increasingly common bone marrow disorder known as myelodysplastic syndrome (MDS).

“Using leading-edge cellular reprogramming techniques in the laboratory, we were able to study two different chromosomal abnormalities found in patients with MDS, a group of disorders in which the bone marrow does not produce enough healthy blood cells,” said Stephen D. Nimer, M.D., Director of the Sylvester Comprehensive Cancer Center and professor of medicine, biochemistry and molecular biology. “Our studies of 20q- and 7q- MDS provide us with new knowledge that will hopefully ultimately lead to our ability to correct the genetic defects that are connected with MDS and acute myeloid leukemia (AML).”

In a study published online March 23 in the prestigious journal Nature Biotechnology, Nimer’s team collaborated with Eirini Papapetrou, M.D., Ph.D., who conducted this work in her lab at the University of Washington and now at the Icahn School of Medicine at Mount Sinai in New York, and with Timothy Graubert, M.D., at Massachusetts General Hospital in Boston, as well as with clinical researchers at Memorial Sloan Kettering Cancer Center in New York, to examine the cells of MDS patients who have lost or deleted chromosome 7 – a condition called del(7q)-. Prior research has found that the bone marrow cells in patients with this genetic defect lack the ability to reproduce healthy blood cells, resulting in anemia, and other low blood counts that lead to susceptibility to infection and bleeding. In approximately 30 percent of MDS patients, this condition progresses to AML, a deadly cancer of the blood.

To determine how this chromosome deletion contributes to the development of MDS, these investigators isolated blood cells from a patient with the chromosome 7 deletion, and turned them into stem cells – a process called the generation of induced pluripotent stem cells (iPSC). These newly created stem cells can be studied for their growth properties and can be induced to become mature blood cells and other types of mature cells.

In MDS patients with the chromosome 7 deletion, Nimer, Papapetrou and collaborators found that those iPSCs also had trouble growing, but eventually were able to correct the genetic problem and become healthy blood cells. “This tells us that the abnormal chromosome is fundamental to MDS,” Nimer said. “By addressing the genetic issues, we hope to be able to develop new treatment strategies for patients with MDS or AML.”

This work is contained in a publication titled “Functional dissection of hemizygous chromosomal deletions with human induced pluripotent stem cell models of myelodysplastic syndromes.” Among the study’s 13 co-authors was Emily K. Dolezal, Director of Research Support at Sylvester. Drs. Nimer and Papapetrou were the senior authors on this journal article.

Nimer was senior author on a second MDS genetic study that focused on chromosome 20q. “Instead of taking blood cells from a patient and turning them into iPSCs, we took embryonic stem cells, eliminated a specific gene located on the 20q chromosome, called L(3)MBTL1, and observed that the stem cells preferentially formed blood cells, and were defective in forming nerve cells,” said Nimer.

“Through this work, we found that certain cellular signaling pathways become hyperactive, which can affect the disease process,” Nimer said. “Therefore, if the signaling pathway can be blocked, we may be able to get those cells under control and potentially improve patient outcomes.”

The study, titled “The Polycomb Group Protein L(3)MBTL1 Represses a SMAD5-Mediated Hematopoietic Transcriptional Program in Human Pluripotent Stem Cells,” was published online March 5 in Stem Cell Reports.

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