A MOZ-TIF2 leukemic mouse model displays KAT6 inhibitor-sensitive H3K23 propionylation and dysregulation of a set of highly active developmental genes [RNA-seq]

Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alteration of these proteins, often enzymes, can be targeted therapeutically. MOZ, a histone acyltransferase, is recurrently fused to coactivators CBP, p300, and TIF2 in cases of Acute Myeloid Leukemia (AML). Using either pharmacological inhibition or targeted protein degradation in a mouse model for MOZ-TIF2-driven leukemia, we show that KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein are necessary for indefinite proliferation in cell culture. Interestingly, MOZ enzymatic activity is selectively required in MOZ-TIF2 cells, as murine MLL-AF9 leukemic cells show no sensitivity to the WM-1119 MOZ inhibitor. MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors, augmenting their high expression. Transcription levels of these genes positively correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr), a recently appreciated histone acylation associated with gene activation. Unexpectedly, we also show that MOZ-TIF2 and MLL-AF9 regulate transcription of largely non-overlapping gene sets, and their cellular models exhibit distinct sensitivities to multiple small molecule inhibitors directed against AML pathways. This is despite the shared genetic pathways of wild-type MOZ and MLL. Overall, our data provide insight into how aberrant regulation of MOZ contributes to leukemogenesis. We anticipate these experiments will inform future work identifying targeted therapies in the treatment of AML and other diseases involving MOZ-induced transcriptional dysregulation. To investigate how MOZ-TIF2 alters hematopoietic transcription, we altered MOZ/MORF and MOZ-TIF2 function through MOZ inhibition via WM-1119 treatment or MOZ-TIF2 degradation through dTAG13 treatment. We extracted nascent RNA or mRNA from mouse LSK cells containing either MOZ-TIF2 or MLL-AF9 and performed differential expression analysis comparing treated vs DMSO (control) cells mRNA was extracted from mouse LSK cells carrying either an MLL-AF9 or MOZ-TIF2 transgene. Cells were treated with either DMSO or 1 uM WM-1119 for 1 hour.