Continued progress in leukemia treatment requires a better understanding of the molecular mechanisms of diseases and pathways that confer resistance to chemotherapy. In general, genes that are now recognized as playing a role in cancer development can be divided into two groups: oncogenes and tumor suppressor genes. Oncogenes are mutated, hyperactive forms that cause normal cells to grow out of control. In contrast, tumor suppressor genes normally keep cells from dividing too quickly or uncontrolled. Thus, when tumor suppressor genes don’t work properly or are absent, cells can grow out of control. Such an inactivation of a tumor suppressor gene can either happen through repression of gene expression or loss of both functional copies of the gene through various mutational pathways.
The retinoblastoma (RB) tumor suppressor gene is such a gene; it is best known for its role in causing the childhood cancer retinoblastoma when both copies of the gene are deleted in retinal cells. The RB gene is also, together with the p53 gene, one of the best-studied tumor suppressor genes in various types of solid cancers. The role of these tumor suppressor genes in normal hematopoiesis, aging and leukemia development has been less well investigated.
We have shown that RB is thus critical for hematopoietic stem and progenitor cell function, localization and differentiation. We will further investigate the block in B-cell differentiation and determine the pathway of loss of self-renewal activity in RB-/- HSCs, and the contribution or loss of RB to disease progression in mouse models of B-cell leukemia.