Abstract 2694: Histone acetyltransferase activity of MOF is required for MLL-AF9 leukemogenesis

Chromosomal rearrangementsof the Mixed-Lineage Leukemia (MLL) gene are found in 5-10% of all patients with acute leukemia and associated with a poor prognosis. MLL-rearrangements are more frequently present in pediatric and infant patients where AF9 is one of the most common fusion partners. In order to identify novel druggabletargets in MLL-AF9 rearranged leukemia, we conducted a chromatin regulator focused RNAi screen in murine MLL-AF9 leukemia cells and found hairpins targeting (K)Lysine Acetyltransferase8 (Kat8, also known as Mof) and the previously identified target BromodomainContaining 4 ( Brd4), to be the most potent suppressors of cell growth. MOF is a histone 4 lysine 16 (H4K16) acetyltransferaseand member of the MYST family of histone acetyltransferases(HATs). MOF has been shown to be crucial for murine embryogenesis and is a cell-type dependent regulator of chromatin state and various cellular processes such as T-cell differentiation, DNA damage response and cell cycle progression. Using a conditional murine Mof knockout system, we studied the role of MOF in MLL-AF9 leukemogenesis in detail. In vitro inactivation of Mof in MLL-AF9 transformed mouse hematopoietic stem and progenitor cells led to impaired colony-forming capacity. The specificity of this phenotype was shown by expression of exogenous full-length Mof, which fully rescued transformed cells from the dramatic phenotype. Inactivation of Mof in vivo, lead to reduced tumor burden and prolonged survival of mice bearing MLL-AF9 leukemia cells. RNA sequencing data comparing MLL-AF9 cells with homozygous Mof loss to a wild type control, showed a significant enrichment of genes within the apoptosis (NES 1.98, FDR-q These results indicate that MOF HAT activity is required for MLL-AF9 leukemia maintenance. Our data further suggest that MOF HAT activity may be a good target for new small molecule inhibitor development for the treatment of patients with MLL-AF9 rearranged leukemia. Citation Format: Daria G. Valerio, Haiming Xu, Chun-Wei Chen, Takayuki Hoshii, Meghan Eisold, Christopher Delaney, Monica Cusan, Aniruddha J. Deshpande, Chun-Hao Huang, Amaia Lujambio, George Zheng, Tej K. Pandita, Scott W. Lowe, Scott A. Armstrong. Histone acetyltransferaseactivity of MOF is required for MLL-AF9 leukemogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2694.