Funded Grants

The role of bmi-1 in neural stem cell self-renewal and neoplastic proliferation

More than 18,000 new cases of malignant cancers of the brain and nervous system will be diagnosed this year alone in the United States. The mortality rate for these cancers remains over 70%. The most aggressive of these cancers, glioblastoma, accounts for nearly half of these cancers. There has been little increase over the past few decades in the survival rate of patients with glioblastoma. Patients rarely live more than 3 years after diagnosis. New insights into the biology and origin of glioblastoma are required to devise more effective therapies.

Emerging work from a number of laboratories suggests that there are remarkable parallels between the proliferation of cancer cells and the proliferation of normal stem cells. Indeed, many cancers may arise from mutations that transform normal stem cells. These findings suggest that we may be able to better understand and treat cancer by better understanding the proliferation and survival of normal stem cells. This raises the possibility of gaining insights into cancers of the central nervous system (CNS) by learning more about normal CNS stem cells.

CNS stem cells persist in the brain throughout life and give rise to new neurons and glia. Very few cells within the adult brain are capable of proliferating, and stem cells are the most proliferative of these cells. Accumulating evidence suggests that the genes that regulate the proliferation of normal stem cells are the same genes that cause cancer when mutated. Unfortunately, we know very little about how the proliferation of normal stem cells is regulated. Nonetheless, many scientists hypothesize that if we could learn more about the proliferation of normal stem cells that we would gain novel insights into how cancer cells co-opt these same pathways to proliferate in an uncontrolled way. This could improve our ability to identify, diagnose, and treat cancer.

Our laboratory has recently discovered that an oncogene called bmi-1 is a critical regulator of the proliferation of normal CNS stem cells. We are proposing to study how bmi-1 promotes the proliferation of CNS stem cells, and whether amplified production of bmi-1 leads to brain cancers such as glioblastoma.

We have discovered that bmi-1 regulates the proliferation of a variety of different types of stem cells, including CNS stem cells, in very similar ways. In fact, bmi-1 appears to promote stem cell proliferation in two ways. First, bmi-1 turns off other genes that directly impair proliferation. The first aim of our research will be to identify the genetic pathway that is turned off in stem cells by bmi-1 to promote proliferation. bmi-1 also appears to turn off genes that initiate the maturation of stem cells into specialized brain cells. Because specialized brain cells, like neurons, usually do not divide, this maturation process eliminates their ability to proliferate. The second aim of our research will be to identify pathways that are turned off by bmi-1 to inhibit the process of maturation. By identifying genes that directly and indirectly inhibit proliferation and that are turned off by bmi-1 in stem cells, we will begin to elucidate the molecular pathways that regulate the proliferation of normal CNS stem cells. These pathways have a major effect on the proliferation of stem cells as in the absence of bmi-1, stem cells become severely depleted and are unable to persist in normal numbers into adult life.

Some of the genes in a pathway that is regulated by bmi-1 have already been shown to be deleted in a surprisingly large proportion of brain cancers. Because these genes impair proliferation, mutations that delete these genes contribute to the ability of cancer cells to proliferate in an uncontrolled way. But nobody has yet examined whether additional brain cancers might be explained by mutations that increase the production of bmi-1. Certain other types of cancer, such as in the blood-forming system, have been linked to increased bmi-1 production. Thus the third aim of our research will be to examine whether bmi-1 production is abnormally increased in a subset of brain cancers. If so, this would begin to explain how these brain cancers develop. Increased production of bmi-1 could make cancer cells unusually aggressive given bmi-1’s powerful ability to turn off many genes that directly and indirectly impair proliferation.

If we identify bmi-1-dependent pathways that regulate the proliferation of CNS stem cells and brain cancer cells it would not only improve our understanding of these important scientific questions, but it would suggest new therapeutic targets that could be exploited in treating brain cancer. For example, bmi-1 turns genes off by modifying the structure of DNA, so its effects might be countered by using drugs that inhibit its ability to modify DNA structure. Most importantly, if brain cancer cells use the same mechanism to proliferate as CNS stem cells then it will be possible to continue to generate novel insights into this mechanism by studying the regulation of stem cell proliferation. Ultimately we hope that it will be possible to exploit our understanding of stem cell proliferation by developing new therapies for brain cancers.