Due to the relatively short life span of the majority of effector hematopoietic cells, it is estimated that the human body generates millions of blood cells every second to maintain homeostasis. Hematopoietic stem cells (HSCs), due to their pluripotent potential and ability to self renew, reside at the top of the hematopoietic hierarchy and at the origin of this massive and constant blood production. Failure to maintain functional HSCs invariably leads to bone marrow failure. Central to the maintenance of functional HSCs are the mechanisms that restrict HSC cell cycle entry. This is exemplified by the facts that the vast majority of adult HSCs are quiescent, and that HSC quiescence is required to replenish the hematopoietic compartment following stresses such as blood loss and infection. Leukemic stem cells (LSCs) and HSCs share similar mechanisms for their maintenance, including their dormant nature. In patients affected by chronic myelogenous leukemia (CML), tyrosine kinase inhibitors (TKI) fail to eradicate LSCs leading to high rates of relapse following treatment cessation. This forces patients to remain on therapy for their lifetime and increases the risk of adverse side effects. In animal models of CML, disrupting LSC quiescence has proven effective at accelerating LSC exhaustion and eradicating residual disease. Despite these facts, our understanding of the molecular mechanisms underlying quiescence in both normal and malignant hematopoietic stem cells remains incomplete. Gene expression studies have revealed that the majority of pro-proliferative cell cycle genes are transcriptionally repressed in HSCs. Silencing these genes are vital for HSC functions; however, the cellular mediators of this repression remain unknown. Sin3B, a scaffold protein for canonical transcriptional repressive complexes, is required for fibroblasts to exit cell cycle following various stimuli. Based on this knowledge, I hypothesized that Sin3B is required for stem cell maintenance through its ability to repress pro-proliferative cell cycle genes. I now demonstrate that Sin3B-/- HSCs are impaired at reconstituting the hematopoietic compartment and have an increased propensity to enter cell cycle. This proposal aims to i) elucidate the Sin3B-dependent transcriptional networks that maintain HSC quiescence and prevent bone marrow failure and ii) test whether Sin3B is similarly required for the maintenance of leukemic stem cells. These studies will provide greater insight into how chromatin-modifying complexes regulate gene expression for the life-long maintenance of HSCs. Furthermore, this proposal will establish whether Sin3B represents a novel drug target to eliminate TKI-resistant LSCs in CML.
Cellular quiescence is vital for the long-term maintenance of both hematopoietic and leukemic stem cells. Uncovering the molecular mechanisms underlying stem cell quiescence will enhance our understanding of the pathways required to prevent bone marrow failure as well as reveal new strategies for the treatment of leukemia.
|Bainor, Anthony J; Deng, Fang-Ming; Wang, Yu et al. (2017) Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence. Cancer Res 77:5339-5348|
|Cantor, David J; David, Gregory (2017) The potential of targeting Sin3B and its associated complexes for cancer therapy. Expert Opin Ther Targets 21:1051-1061|
|Cantor, David J; David, Gregory (2017) The chromatin-associated Sin3B protein is required for hematopoietic stem cell functions in mice. Blood 129:60-70|