Scientists long believed that these diseases were caused by disruptions in the normal cycle of blood stem cells that prompted them to morph into progenitor cells, an intermediate phase when stem cells have been programmed to become a certain type of tissue cell, but have not fully matured into that form. But two new studies published this week in the journal Cell indicate that outside factors rather than flawed cells may be to blame. Specifically, scientists found that blood stem cells may go haywire because of defects in the bone marrow, where they are manufactured.
"Our findings are completely clinically relevant and may change the way such patients are diagnosed and treated in the future," says Louise Purton, a stem cell biologist with appointments at Massachusetts General Hospital in Boston and the Peter MacCallum Cancer Center in East Melbourne, Australia. "The fact that the microenvironment (where stem cells are created and stored) was the sole inducer of the disease was a completely unexpected result. Our studies are the first to show that this is occurring, and there is clinical evidence that some patients who are transplanted with healthy donor cells develop a blood disease that is solely [of] donor origin, yet the donor remains healthy."
The teams—Purton's and another, led by pediatric oncologist Stuart Orkin of Harvard's Dana-Farber Cancer Institute—determined that the cells' microenvironment could induce the disorders in mice whose bone marrow was deprived of one of two proteins: retinoic acid receptor gamma (RARγ), a receptor protein that binds vitamin A and the tumor suppressor retinoblastoma protein. Instead of remaining at bay like normal stem cells until needed by the body, those in the protein-deficient environs differentiated into progenitor cells that matured into white or red blood cells or into platelets, osteoblasts (cells that become bone) or osteoclasts (cells that naturally break down bone) without reproducing.
Purton's group discovered last year that mice lacking RARγ receptors in their blood and bone marrow cells had three times fewer blood stem cells than normal mice. The reason: the stem cells had somehow matured too quickly without dividing and reproducing. The team observed that those mice appeared to have symptoms similar to the ones produced in people with myeloproliferative diseases, Purton says, and that their prematurely differentiating cells flooded the blood and settled in other parts of the body, such as the spleen, which became enlarged as it often does in such disorders.
Purton's team recreated these conditions in their new study, once again removing the RARγ receptors and inducing the myeloproliferative syndrome state in mice. They then injected bone marrow from normal mice (with RARγ receptors intact) into the knockout mice. "In this instance, [in which] the blood cells all contain RARγ [and] the microenvironment completely lacks RARγ," Purton says "the myeloproliferative syndrome occurs very rapidly, proving that this disease is solely induced by the microenvironment."
In the second new study, Orkin's group inactivated retinoblastoma protein in a group of mice. According to Orkin, this protein has been known for 20-plus years as a key regulator of cell cycle, and is believed to be "deranged" in many cancers. They found that depriving bone marrow cells of retinoblastoma protein was enough to cause stem cells to progress into early-progenitors, or cells that have already differentiated instead of staying versatile. These excess cells then migrate to the spleen and flood other parts of the body causing the disorders mentioned above.
Orkin says the next step in this research is to determine the cellular interactions that take place between the mature cells of the bone marrow and the stem cells that are produced and live there.
Researchers say there's no question that the cells' microenvironment contributes to precancerous blood cell disorders. But they note that it is still not clear how exactly it is able to speed up stem cell differentiation and aging. "I think this work suggests that in this kind of disease that may evolve over time," Orkin says, "you can't just focus on one component [such as the stem cells themselves] while ignoring the other."