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MOZ regulates B cell progenitors and, consequently, Moz haploinsufficiency dramatically retards MYC-induced lymphoma development


Sheikh, BN; Lee, SC; El-Saafin, F; Vanyai, HK; Hu, Y; Pang, SH; Grabow, S; Strasser, A; Nutt, SL; Alexander, WS; Smyth, GK; Voss, AK; Thomas, T
2015-03-19
2015-01-20
Blood
Journal Article
125
12
1910-21
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. Here we report the role of wild-type MOZ in regulating B cell progenitor proliferation and hematopoietic malignancy. In the Emu-Myc model of aggressive pre-B/B-cell lymphoma, loss of just one allele of Moz increased the median survival of mice 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, MLL1 and MLL1 co-factor 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.
ASH
Development and Cancer; Molecular Immunology; Molecular Genetics of Cancer; Cancer and Haematology; Bioinformatics
10.1182/blood-2014-08-594655
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2015-01-27 10:32:57 Last Modified 2016-02-09 05:25:53