title: Loss of p300 accelerates MDS-associated leukemogenesis.
abstract: The role that changes in DNA methylation and histone modifications have in human malignancies is poorly understood. p300 and CREB-binding protein (CBP), two distinct but highly homologous lysine acetyltransferases, are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis ofNup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 has a pivotal role in blocking the transformation of MDS to acute myeloid leukemia, a role distinct from that of CBP.
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: G
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: T
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Human Genetics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: F
authors.initials: F
authors.lastname: Lai
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: N
authors.initials: N
authors.lastname: Man
authors.affiliation: Department of Medicine, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York,NY,USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: S
authors.initials: S
authors.lastname: Greenblatt
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: P-J
authors.initials: PJ
authors.lastname: Hamard
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: K
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Public Health Sciences, Division of Biostatistics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Public Health Sciences, Division of Biostatistics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: C
authors.initials: C
authors.lastname: Martinez
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: M
authors.initials: M
authors.lastname: Tadi
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: F-C
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Department of Human Genetics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Shiekhattar
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.|Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000502:physiology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007942:Leukemia, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C521093:NUP98-HOXD13 protein, human; D015514:Oncogene Proteins, Fusion; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse