The research, led by graduate student Benjamin J. Frisch in the James P. Wilmot Cancer Center laboratory of corresponding author Laura M. Calvi, M.D., is featured in the journal Blood. It is accompanied by an editorial – “Bad to the Bone” -- written by another leading investigator in the field, Steven W. Lane, M.D., of Queensland Institute of Medical Research. Lane says that the URMC’s unexpected laboratory finding provokes new clinical questions, such as whether screening for osteoporosis could provide any useful information for how to manage acute leukemia in newly diagnosed patients.
Leukemia is a devastating disease that results in the disruption of normal blood production. Blood stem cells (hematopoietic stem cells or HSCs) give rise to all mature blood cells and maintain a balance of self-renewal and expansion. However, in this study, even when leukemia is barely traceable in the blood, leukemic cells implant in the bone marrow and attack the body’s natural process of making healthy blood stem cells.
In this hematopoietic microenvironment, or niche, investigators have been searching for clues. In 2003 Calvi introduced the concept that osteoblasts, which actively work to form bone in this same microenvironment, might have a key role in expanding and supporting the production of normal blood cells. Published in the journal Nature, that study served as the basis for the current investigation.
In this study, leukemia caused low-level and widespread bone thinning and bone loss, similar to osteoporosis, particularly in the long bones. Preliminary lab experiments showed that treatment with bisphosphonates, a commonly used class of drugs for people who suffer from bone loss, partially restored bone loss in mice with leukemia.Leukemia results in the expression of a protein, known as CCL3, which slows bone formation. Thus, elevated CCL3 levels in leukemia make it a tempting treatment target. Theoretically, newer drugs that block the CCL3 pathway might be able to restore the low-level, net loss of bone observed in many leukemia patients. A few drug compounds that act on the CCL3 pathway are under study in early-stage clinical trials, Frisch said.
“Our findings are quite provocative and we hope they will lead to new approaches to promote normal blood production in patients with blood cancers,” said Calvi, associate professor of Medicine. “Because the loss of normal hematopoietic function is the chief cause of serious illness and death among leukemia patients, it is critical that we understand all aspects of how this occurs and find new strategies to accelerate the recovery of these defects.”
Funding was provided by the Wilmot Scholar Cancer Research Award and the Pew Scholar in Biomedical Sciences Award. Co-authors include John M. Ashton, Ph.D., URMC Department of Genetics; Lianping Xing, Ph.D., URMC Department of Pathology and Laboratory Medicine; Michael W. Becker, M.D., URMC Department of Medicine, and Craig T. Jordan, Ph.D., the Philip and Marilyn Wehrheim Professor of Medicine at Wilmot.For Media Inquiries:
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