TY - JOUR
T1 - MOZ regulates B-cell progenitors and, consequently, Moz haploinsufficiency dramatically retards MYC-induced lymphoma development
AU - Sheikh, Bilal N.
AU - Lee, Stanley C.W.
AU - El-Saafin, Farrah
AU - Vanyai, Hannah K.
AU - Hu, Yifang
AU - Pang, Swee Heng Milon
AU - Grabow, Stephanie
AU - Strasser, Andreas
AU - Nutt, Stephen L.
AU - Alexander, Warren S.
AU - Smyth, Gordon K.
AU - Voss, Anne K.
AU - Thomas, Tim
PY - 2015/3/19
Y1 - 2015/3/19
N2 - 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 Eν-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-MYCoverexpression, 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.
AB - 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 Eν-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-MYCoverexpression, 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.
UR - http://www.scopus.com/inward/record.url?scp=84925379433&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-08-594655
DO - 10.1182/blood-2014-08-594655
M3 - Article
C2 - 25605372
SN - 0006-4971
VL - 125
SP - 1910
EP - 1921
JO - Blood
JF - Blood
IS - 12
ER -