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February 15, 2012

Research finds leukemia cells are ‘Bad to the Bone’

Medical Center researchers have discovered new links between leukemia cells and cells involved in bone formation, offering a fresh perspective on how the blood cancer progresses and raising the possibility that therapies for bone disorders could help in the treatment of leukemia.

The research, led by graduate student Benjamin Frisch in the Wilmot Cancer Center laboratory of corresponding author Laura Calvi, 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 Lane of Queensland Institute of Medical Research. Lane says that the Medical Center’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 disrupts 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 the 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 the 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.

Frisch began focusing on the impact of the leukemia cells, which reside on the inside surface of bones adjacent to bone marrow activity. Until now, according to the Blood paper, no one had defined the important interactions that take place between leukemia cells and osteoblasts (bone forming cells) and osteoclasts, which continually break down bone.

In the 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 says.

“Our findings are quite provocative, and we hope they will lead to new approaches to promote normal blood production in patients with blood cancers,” says 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. Coauthors include John Ashton, Department of Genetics; Lianping Xing, Department of Pathology and Laboratory Medicine; Michael Becker, Department of Medicine, and Craig Jordan, the Philip and Marilyn Wehrheim Professor of Medicine at Wilmot.

Read more about the study at www.urmc.rochester.edu/news/story/index.cfm?id=3399.

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