A MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes

Author:

Smolko Anne E.12,Sullivan Daniel W.12,Olsen Sarah Naomi3,Kang Hyuckjoon12,Whedon Samuel D.14,Baell Jonathan B.5,Cole Philip A.14,Armstrong Scott A.6,Kuroda Mitzi I.12ORCID

Affiliation:

1. Department of Medicine, Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115

2. Department of Genetics, Harvard Medical School, Boston, MA 02115

3. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215

4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115

5. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia

6. The Division of Hematology/Oncology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02215

Abstract

Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alterations 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. MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors, augmenting their high expression. Furthermore, transcription levels in MOZ-TIF2 cells 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 unique 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 that these experiments will inform future work identifying targeted therapies in the treatment of AML and other diseases involving MOZ-induced transcriptional dysregulation.

Funder

HHS | NIH | National Institute of General Medical Sciences

American Cancer Society

HHS | NIH | NCI | Center for Cancer Research

Leukemia and Lymphoma Society

Charles A. King Trust

Publisher

Proceedings of the National Academy of Sciences

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