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

Abstract

Key Points• Regulation of genes required for B-cell progenitor proliferation is exquisitely dependent on Moz gene dosage.• Loss of one Moz allele delays the onset of MYC-driven lymphoma by 3.9-fold.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 Em-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. (Blood. 2015; 125(12):1910-1921

Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

“…In support of these findings, wild-type MOZ was recently shown to be specifically upregulated by an oncogenic p53 mutant (75). Furthermore, MOZ is critical for the proliferation of B-cell progenitors, and therefore, Moz haploinsufficiency delays the development of MYC-induced lymphoma (76). In addition to hematopoietic malignancy, recurrent amplification of the MOZ and/or MORF genes has been identified in solid tumors, including breast cancer, ovarian cancer, uterine cervix cancer, lung adenocarcinoma, colon and rectal adenocarcinomas, and medulloblastoma (13,14).…”

Histone H3 Lysine 9 Acetylation Obstructs ATM Activation and Promotes Ionizing Radiation Sensitivity in Normal Stem Cells

“…We have thus elucidated epigenetic and molecular signaling rheostats that pluralistically regulate and collectively promote IR hypersensitivity of stem cells. Interestingly, use of MOZ inhibition has been suggested earlier for the treatment of certain types of lymphoma and leukemia (Sheikh et al., 2015b) as well as for a potential induction of senescence in cancer stem cells (Perez-Campo et al., 2014). The expression of mutated MOZ has been associated with the formation of medulloblastoma (Wu et al., 2012).…”

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

“…Moreover, the MOZ and MORF genes have both been identified as top-ranking targets amplified in different types of cancer [102]. Mouse studies indicate that Moz is required for lymphoma development induced by Myc [68] and its loss leads to senescence of mouse embryonic fibroblasts and neural stem cells [70,71]. All of these support that MOZ has an oncogenic role.…”

“…Compared to wild-type littermates, the resulting homozygotes display shortened lifespan, low body weight, small thymus and spleen, and proliferation defects in various hematopoietic progenitors [66], supporting the importance of the acetyltransferase activity of Moz in vivo. Moreover, the mouse Moz gene is required for normal B cell development, as well as for optimal lymphoma development induced by Myc [68,69]. In addition, loss of Moz leads to senescence of mouse embryonic fibroblasts and neural stem cells [70,71].…”