Children with Down syndrome (DS) are at substantial risk of developing acute leukemia, which suggests that there are leukemia promoting genes on chromosome 21. Chromatin Assembly Factor 1B (CHAF1B), which resides in the DS critical region, is a member of the heterotrimeric CAF1 chromatin assembly complex that is responsible for depositing H3/H4 heterodimers at the replication fork during S-phase. CHAF1B levels are elevated in DS-AML patient samples, as well as non-DS AML cell lines and primary AML samples when compared to healthy samples. While elevated expression is correlated with poor prognosis in most tumors studied, the mechanism by which CHAF1B promotes leukemogenesis is unknown. My preliminary data show that CHAF1B is required to maintain the undifferentiated state of MLL-AF9 leukemic cells through a novel non - canonical transcriptional regulatory function. In this proposal, I will determine the mechanism of CHAF1B-dependent maintenance of leukemic stem cells. The central hypothesis is CHAF1B acts as a transcriptional repressor, maintaining leukemic stem cells by (1) competing for chromatin occupancy with transcriptional activators of myeloid differentiation genes and (2) cooperating with transcriptional repressors of myeloid differentiation genes. In Aim 1, I will explore how CHAF1B blocks differentiation by competing for chromatin occupancy with transcription factors that activate myeloid differentiation genes, and how the competition with these factors leads to reduced transcription of differentiation genes. In Aim 2, I will focus on how CHAF1B negatively regulates transcription by cooperating with LSD1, an H3K4me3 demethylase that is required for MLL-rearranged AML, at promoters and enhancers of differ entiation genes. Finally, in Aim 3, I will establish CHAF1B as a therapeutic target in AML by determining how inhibiting its activity affects the growth of hematologic tumors in vivo and primary human patient samples. My ultimate goal is to use the information gained during the K99/R00 award to develop novel small molecule compounds that can block CHAF1B function and control AML tumors in vivo by differentiation.
|Effective start/end date||7/1/19 → 6/30/21|
- National Cancer Institute (1K99CA230314-01A1)
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