When blood-forming stem cells misbehave, causing pre-cancerous conditions that can sometimes even progress to leukemia, the problem might not always lie with them. Rather, two studies in the June 15 issue of the journal Cell reveal that a bad environment might be to blame.
Both reports show that defects in the bone marrow--where blood cells are made--can spawn such pre-cancerous blood disorders in mice. Previously, such myeloproliferative syndromes were thought to be rooted in the blood cells themselves.
"We show that the bone marrow microenvironment can make the blood cells become abnormal, like a type of pre-leukemic disease," said Louise Purton, who is affiliated with Peter MacCallum Cancer Centre in Australia, Massachusetts General Hospital, and the Harvard Stem Cell Institute. Such pre-cancerous conditions are often difficult to treat in humans, she added, mainly because not much is known about what causes the blood cells to act out.
"The defect we see isn't intrinsic to the blood cells themselves," added Stuart Orkin, a Howard Hughes Medical Institute investigator at Children's Hospital Boston and Chairman of Pediatric Oncology at the Dana-Farber Cancer Institute. "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 its important role in regulating the self-renewal and differentiation of blood stem cells, also known as hematopoietic stem cells (HSCs), the bone marrow microenvironment has been proposed to consist of various other niches or hematopoietic inductive microenvironments--areas of the bone marrow that are highly specialized for the development of different kinds of maturing hematopoietic cells, Purton explained. This concept has been supported by the recent identification of specific niches for blood cells including B lymphocytes and megakaryocytes in the bone marrow, she said.
Purton's team found in an earlier study that mice lacking the retinoic acid receptor ãRARã one of three receptors that respond to a derivative of vitamin A, experience a 3-fold reduction in the number of HSCs. Now, her team has found that the animals also develop myeloproliferative disease, in which the stem cells in bone marrow produce too many blood cell progenitors and blood cells.
Unexpectedly, they reported, transplant studies revealed that this disease was caused by the bone marrow deficiency. Bone marrow from healthy mice transplanted into mice with the RARã-deficient microenvironment rapidly developed the blood disease, they showed, evidence that the microenvironment can be the sole cause of hematopoietic disorders.
Meanwhile, Orkin's team set out to examine 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 said. "It deregulates the process of stem cell differentiation and the animals get myeloproliferative disease."
As in Purton's study, Orkin's team found that the animals' condition resulted not from faults within HSCs themselves but rather as a consequence of an Rb-dependent interaction between myeloid-derived cells and their microenvironment.
The new understanding could help pave the way to novel therapies, according to the researchers. 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.
"At the moment, most doctors focus only on the blood cell as being the cause of the disease," Purton said. "Hopefully, the microenvironment will now also be considered as a potential cause, which might lead to better treatments for these patients in the future."
The findings emphasize the importance of environmental considerations for the success of stem cell therapies more generally, Orkin said. "For bone marrow transplantations to work, you will need a decent environment in which to put them," he said. "If you put stem cells in an environment that can't support them, it will be as if you didn't transplant them at all."
(Walkley et al.-1)
The researchers include Carl R. Walkley and Jeremy M. Shea of Dana-Farber Cancer Institute, Children's Hospital Boston, Harvard Stem Cell Institute, and Harvard Medical School in Boston, MA; Natalie A. Sims of The University of Melbourne in Victoria, Australia; Louise E. Purton of Massachusetts General Hospital, Harvard Stem Cell Institute in Boston, MA; Stuart H. Orkin of Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Children's Hospital Boston, Harvard Stem Cell Institute, and Harvard Medical School in Boston, MA.
This work was supported in part by a Center of Excellence in Molecular Hematology Award from the NIH-NIDDK (S.H.O). C.R.W is a Special Fellow of the Leukemia & Lymphoma Society, and S.H.O is an Investigator of the Howard Hughes Medical Institute.
(Walkley et al.-2)
The researchers include Carl R. Walkley of Peter MacCallum Cancer Centre and University of Melbourne in Victoria, Australia, Dana-Farber Cancer Institute and Children's Hospital, and Harvard Medical School, Boston, MA; Gemma Haines Olsen, Sebastian Dworkin, Stewart A. Fabb, and Jeremy Swann of Peter MacCallum Cancer Centre in Victoria, Australia; Grant A. McArthur of Peter MacCallum Cancer Centre and University of Melbourne in Victoria, Australia; Susan V. Westmoreland of Massachusetts General Hospital, Boston, MA; Pierre Chambon of CNRS/INSERM/ULP, College de France in Strasbourg, France; David T. Scadden and Louise E. Purton of Massachusetts General Hospital, Harvard Stem Cell Institute, Boston, MA.
This work was supported in part by grants from the Cancer Council of Victoria (L.E.P.), the National Health and Medical Research Council (L.E.P.), National Institutes of Health (NIH) DK84551 (D.T.S.), and NIH DK71773 (L.E.P.). C.R.W. was a recipient of an Australian Postgraduate Award and is a Special Fellow of the Leukemia and Lymphoma Society.
Walkley et al.: "Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment." Publishing in Cell 129, 1081--1095, June 15, 2007. DOI 10.1016/j.cell.2007.03.055
Walkley et al.: "A Microenvironment-Induced Myeloproliferative Syndrome Caused by Retinoic Acid Receptorg Deficiency." Publishing in Cell 129, 1097--1110, June 15, 2007. DOI 10.1016/j.cell.2007.05.014
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