The debate over the relative power of nature vs. nurture to control the course human life extends all the way down to the level of our cells. According to new findings from HMS, an immature cell’s nurturing surroundings have a surprising capacity to turn that cell cancerous.
Researchers in the lab of David Scadden, the Gerald and Darlene Jordan professor of medicine at HMS and Massachusetts General Hospital and director of the MGH Center for Regenerative Medicine, have discovered a mechanism by which stem cells in bone marrow are mutated, setting the stage for their transformation to leukemia. The trouble can be traced, the researchers say, to cells next door—in the microenvironment that controls bone marrow formation.
Trouble at HomeFor years, scientists believed that numerous genetic mutations were required to initiate cancer in cells that make up the body’s mature tissues. In the case of the blood and lymph systems, mature red blood cells and infection-fighting lymphocytes develop from blood-forming stem cells (hematopoetic stem cells, or HSCs) in bone marrow. To maintain a delicate balance between stem cells that self-renew and those that go on to form tissues, these cells’ microenvironment, or niche, must tightly regulate them. Healthy blood formation and a vigorous immune system depend on it.
All it takes, however, is just one or two mutations to enable stem cells to exploit their microenvironment rather than take direction from it. In recent years, scientists have learned that some cancers arise and spread through the action of a small population of cells that at some point have mutated. Such cells resemble stem cells and have come to be known as cancer stem cells.
In the April 8 issue of Nature, Scadden, who is also co-director of the Harvard Stem Cell Institute and co-chair of Harvard’s Department of Stem Cell and Regenerative Biology, and his colleagues describe one source of these mutations. In mice, they show that a white blood cell cancer called acute myeloid leukemia (AML) can be induced by a defect in the HSC microenvironment.
MicroRNA ConnectionTo craft an unhealthy microenvironment, postdocs Marc Raaijmakers and Siddhartha Mukherjee deleted a master regulator gene, dicer1, from one type of HSC niche cell, the osteoprogenitors. Dicer1 is required for gene regulation by microRNAs, tiny strands of RNA that vary the amount of protein a gene produces. Through microRNA production, Dicer1 controls the fate of blood-forming stem cells.
With this key gene deleted, myelodysplastic syndrome (MDS) emerged—a preleukemic disease in which immature blood cells accumulate after HSC differentiation becomes blocked. MDS characteristics could not be transferred, however, when bone marrow cells from mutant mice were transplanted into a healthy niche. Continuous, aberrant signaling from the niche appears to be needed to sustain the disease.
On the other hand, healthy bone marrow cells transplanted into a mutated niche couldn’t cure the condition. Eventually the mice developed AML, having acquired chromosomal abnormalities even in the presence of intact Dicer1. These findings suggest that microenvironment alterations set the stage for MDS and AML, with cells within the microenvironment—the osteoprogenitors—being the primary enablers.
As the researchers reported, “The findings of this study … point to the microenvironment as the site of the initiating event that leads to secondary genetic changes in other cells.”
Limitations of TransplantsTo pinpoint some of the genetic changes underlying MDS and AML, the researchers measured gene expression levels in the bone-forming cells of their mutant mice, as compared to healthy mice. After identifying significant changes in more than 600 genes, they focused on one because of its link to human disease: the gene sbds. Sbds is associated with Shwachman-Diamond syndrome, a form of bone marrow failure that often leads to MDS and secondary AML.
Deleting sbds from osteoprogenitors reproduced many of the same disease characteristics of the Dicer1 knockout mice, the researchers found. Although not all changes observed in the Dicer1 mutants can be attributed to this single gene, the results implicate osteoprogenitors in this syndrome—and may give clinicians insight as to why treating the syndrome is so difficult. A bone marrow transplant, for example, may be unable to cure the disease, so long as the microenvironment is defective.
The findings raise the prospect of treating the niche itself, said Raaijmakers. “Future work will focus on identifying microRNAs and collaborating molecules, and on determining their relevance to human disease.”
“This adds an exciting and provocative new role for the niche as a contributor to leukemia formation,” according to George Daley, the Samuel E. Lux IV professor of hematology and director of the Stem Cell Transplantation program at Children’s Hospital Boston. “It also represents another surprising insight from the Scadden lab regarding the critical cross-talk between stem cells and their local environs.”
For more information, students may contact David Scadden at dscadden@mgh.harvard.edu.
Conflict Disclosure: David Scadden is a consultant and stockholder for Fate Therapeutics.
Funding Source: The National Institutes of Health; the authors are solely responsible for the content of this work.
