Hematopoietic stem cells (HSCs) in the bone marrow must maintain a constant production of effector blood cells to maintain homeostasis. Key to this is the ability for HSCs, at a population level, to self-renew and maintain quiescence. Central to the maintenance of quiescence and to a functional stem cell pool is regulation of cell cycle entry and exit. Many repressive chromatin-modifying complexes exist that target genes related to proliferation and DNA replication. Perturbations in the maintenance of quiescence or differentiation can lead to bone marrow failure or malignant transformation. We have recently demonstrated that the chromatin scaffolding protein Sin3B is essential for the maintenance of functional HSCs in mice. Sin3B recruits histone deacetylases and through interaction with sequence specific transcription factors modulates local chromatin at discrete genomic loci and represses transcription. Loss of Sin3B diminishes HSCs ability to maintain quiescence and properly differentiate in a competitive transplantation setting. This proposal seeks to understand the Sin3B- dependent transcriptional network necessary for maintenance of HSC function. Additionally, we seek to translate these studies to Acute Myeloid Leukemia, a malignancy characterized by rapid proliferation of blasts that are blocked in differentiation. Specifically, it is thought that patients relapse due to the presence of chemotherapy- resistant Leukemic Stem Cells (LSCs). These LSCs have many similarities to HSCs including quiescence and self-renewal properties, which is hypothesized to be responsible for their resistance to conventional chemotherapy. We propose to understand the role Sin3B plays in maintaining AML LSCs and to determine if targeting of Sin3B presents a novel therapeutic strategy to sensitize LSCs to treatment. This proposal aims to couple acute deletion of Sin3B with chemotherapy treatment to assess if relapse in AML can be abrogated through selective targeting of LSCs.
Cellular quiescence, a temporary form of cell cycle exit, is important for many stem cell compartments to maintain long term function. Understanding the regulation of quiescence in hematopoietic stem cells will lead to new strategies to deal with bone marrow failure and for the treatment of leukemia.
