title: MOZ regulates B-cell progenitors and, consequently, Moz haploinsufficiency dramatically retards MYC-induced lymphoma development.
abstract: 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 Eμ-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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Bilal N
authors.initials: BN
authors.lastname: Sheikh
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Stanley C W
authors.initials: SC
authors.lastname: Lee
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Farrah
authors.initials: F
authors.lastname: El-Saafin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Vanyai
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Swee Heng Milon
authors.initials: SH
authors.lastname: Pang
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Voss
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, and.
authors.forename: Tim
authors.initials: T
authors.lastname: Thomas
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057895:Haploinsufficiency; D051548:Histone Acetyltransferases / Q000235:genetics*; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D013234:Stem Cells / Q000166:cytology*; D014158:Transcription, Genetic
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse