Journal
BLOOD
Volume 125, Issue 12, Pages 1910-1921Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-08-594655
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Funding
- National Health and Medical Research Council (NHMRC) [1030704, 1008699, 1010851]
- NHMRC program [1054618, 1016647, 1016701]
- NHMRC [1058892, 1058344, 1003435, 575512, 1020363]
- Lady Tata Research Award
- Cancer Council Victoria postdoctoral fellowship
- Leukemia and Lymphoma Society [7001-13]
- Australian Research Council
- Australian Government's NHMRC
- Australia Cancer Research Fund
- Victorian State Government
- National Health and Medical Research Council of Australia [575512, 1058892, 1058344] Funding Source: NHMRC
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The histone acetyltransferase MOZ (MYST3, KAT6A) is the target of recurrent chromosomal translocations fusing the MOZ gene to CBP, p300, NCOA3, or TIF2 in particularly aggressive cases of acute myeloid leukemia. In this study, we report the role of wild-type MOZ in regulating B-cell progenitor proliferation and hematopoietic malignancy. In the E mu-Myc model of aggressive pre-B/B-cell lymphoma, the loss of just one allele of Moz increased the median survival of mice by 3.9-fold. MOZ was required to maintain the proliferative capacity of B-cell progenitors, even in the presence of c-MYC overexpression, by directly maintaining the transcriptional activity of genes required for normal B-cell development. Hence, B-cell progenitor numbers were significantly reduced in Moz haploinsufficient animals. Interestingly, we find a significant overlap in genes regulated by MOZ, mixed lineage leukemia 1, and mixed lineage leukemia 1 cofactor menin. This includes Meis1, a TALE class homeobox transcription factor required for B-cell development, characteristically upregulated as a result of MLL1 translocations in leukemia. We demonstrate that MOZ localizes to the Meis1 locus in pre-B-cells and maintains Meis1 expression. Our results suggest that even partial inhibition of MOZ may reduce the proliferative capacity of MEIS1, and HOX-driven lymphoma and leukemia cells.
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