Fellowship in support of Andrew Volk: The role of CHAF1B in maintaining the undifferentiated state of myeloid leukemic stem cells

Acute myeloid leukemia (AML) is an aggressive form of blood cancer with a poor prognosis and few effective treatments. Children with Down Syndrome (DS) have a substantially elevated risk of developing AML, suggesting that some of the genes contained within the DS critical region of chromosome 21 are leukemogenic. I recently determined that the DS critical region gene CHAF1B (p60 component of the CAF1 chromatin assembly complex) is essential for AML development. CHAF1B is trisomic in DS-related leukemias and is overexpressed in most AMLs as well as most other types of cancer. CHAF1B is a chaperone protein primarily responsible for facilitating replication-linked nucleosome assembly. Using my new inducible Chaf1b knockout mice, I determined that CHAF1B blocks the differentiation of myeloid leukemia cells. CHAF1B exerts this function by directly binding chromatin and accumulating at the promoters and enhancers of pro-differentiation genes. My preliminary data suggests this accumulation of CHAF1B functionally maintains the undifferentiated state of AML cells by blocking the occupancy of CEBPA, a pro-differentiation factor that is commonly inactivated in primary AMLs. My long-term goal is to use this information to develop new anti-leukemic therapies based on targeting CHAF1B. In this proposal, I will (1) investigate the mechanism by which CHAF1B exerts its anti-differentiation function and (2) establish CHAF1B as a broadly-applicable target for anti-AML therapy.