Researchers at Montefiore Einstein Comprehensive Cancer Center (MECCC) have discovered a mechanism that disrupts red blood cell production in myelodysplastic syndromes (MDS), a group of bone marrow disorders marked by chronic anemia and an increased risk of leukemia. In a paper published May 13 in Nature Communications, Amit Verma, M.B.B.S., Srinivas Aluri, Ph.D., and colleagues show how elevated levels of the signaling protein TGF-β1 interfere with normal red blood cell production, contributing to the pre-cancerous condition.

In MDS, immature blood cells in the bone marrow do not mature properly, resulting in low levels of healthy blood cells. Although the underlying molecular mechanism is not well understood, a family of signaling proteins called transforming growth factor-beta (TGF-β) have been implicated. Using mouse models and human samples, the MECCC researchers found that  increased levels of the variant TGF-β1 reduced cell division, increased cell death, and caused immature blood-cell precursors to develop prematurely. Together, these changes impaired red blood cell production.

The research team also discovered that TGF-β1 changes how certain genes involved in red blood cell development are turned on and off. In addition, it alters how DNA is organized inside cells, disrupting normal cell growth and limiting the number of immature cells that can develop into red blood cells.

The authors further reported that blocking the TGF-β1 pathway using a drug that inhibits one of its receptors improved red blood cell production. These findings suggest that targeting this pathway could offer a new therapeutic approach for MDS.

Dr. Verma, the senior author of the study, is chair of oncology at Montefiore Einstein and associate director of translational medicine at MECCC. Dr. Aluri is a research assistant professor of oncology and of medicine, is the lead author.