Precancerous blood diseases can be products of their environment
New understanding may pave the way to novel therapies
June 15, 2007
Stuart Orkin, MDWhen blood-forming stem cells misbehave, causing precancerous conditions, a bad environment may be to blame, report two studies in the June 15 issue of the journal Cell.
Myeloproliferative syndromes -- in which blood-forming stem cells produce too many blood cell progenitors and blood cells -- are often difficult to treat and sometimes progress to leukemia. They were previously thought to be rooted in the blood stem cells themselves, but the two new reports show that defects in the bone marrow, where blood cells are made, can spawn pre-cancerous blood disorders in mice.
"The defect we see isn't intrinsic to the blood cells themselves," says Stuart Orkin, MD, a Howard Hughes Medical Institute investigator at Children's Hospital Boston and Chairman of Pediatric Oncology at the Dana-Farber Cancer Institute, and senior investigator on one of the studies. "It's a result of the interaction of the blood and support cells in bone marrow. We didn't predict that at all."
In addition to regulating the self-renewal and differentiation of blood stem cells, bone marrow has been proposed to contain other areas highly specialized for the development of particular kinds of maturing blood cells. This concept has been supported by the recent identification of specific niches for blood cells including B lymphocytes and megakaryocytes in the bone marrow, notes Louise Purton, PhD, of Massachusetts General Hospital, who led the second study.
Orkin's team examined the role of so-called retinoblastoma protein (Rb) -- a critical player in controlling the cell cycle -- in blood cell development. "In the absence of Rb, blood stem cells leave the bone marrow and end up in the spleen and other places," Orkin says. "Rb deregulates the process of stem cell differentiation and the animals get myeloproliferative disease."
The disease arose not from faults within the blood-forming stem cells themselves, Orkin's team found, but rather as a consequence of an Rb-dependent interaction between myeloid-derived cells and their immediate environment.
Purton's team built on an earlier study that found that mice lacking the retinoic acid receptor RAR-gamma, one of three receptors that respond to a derivative of vitamin A, experience a three-fold reduction in the number of blood stem cells. In new studies, her team found that the animals also develop myeloproliferative disease. When bone marrow from healthy mice was transplanted into mice with the RAR-gamma-deficient microenvironment, the disease persisted -- evidence that the local environment can be the sole cause of hematopoietic disorders.
The new understanding of precancerous blood diseases could help pave the way to novel therapies, the researchers say. For instance, the findings provide an explanation for why normal blood-forming stem cells transplanted into patients with the myeloproliferative condition sometimes take on the characteristics of the disease they were meant to cure.
More generally, the findings emphasize the importance of environmental considerations for the success of stem cell therapies, Orkin says. "For bone marrow transplantation to work, you will need a decent environment in which to put the blood stem cells," he says. "If you put them in an environment that can't support them, it will be as if you didn't transplant them at all."
Carl R. Walkley, PhD, of the Department of Hematology-Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, was first author on the Orkin study and co-first author on the Purton study with Gemma Haines Olsen of the Peter MacCallum Cancer Center (Melbourne, Australia). The work was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, the Cancer Council of Victoria and the National Health and Medical Research Council.
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