title: NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function.
abstract: In this report, we show that expression of a NUP98-PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and preleukemic tissues display a stem cell-like expression signature, including Hoxa, Hoxb, and Meis1 genes. The PHF23 plant homeodomain (PHD) motif is known to bind to H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein binds to chromatin at a specific subset of H3K4me3 sites, including at Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD motifs to H3K4me3, rapidly and selectively killed NP23-expressing myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98-JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3.
authors.affiliation: 1Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda; 2Department of Pathology, Johns Hopkins University, Baltimore, Maryland; 3Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin; and 4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
authors.forename: Sheryl M
authors.initials: SM
authors.lastname: Gough
authors.forename: Fan
authors.initials: F
authors.lastname: Lee
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.forename: Yeulin J
authors.initials: YJ
authors.lastname: Zhu
authors.forename: Marbin
authors.initials: M
authors.lastname: Pineda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Onozawa
authors.forename: Yang Jo
authors.initials: YJ
authors.lastname: Chung
authors.forename: Sven
authors.initials: S
authors.lastname: Bilke
authors.forename: Elise K
authors.initials: EK
authors.lastname: Wagner
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.forename: Yi
authors.initials: Y
authors.lastname: Ning
authors.forename: Bowen
authors.initials: B
authors.lastname: Xu
authors.forename: Gang Greg
authors.initials: GG
authors.lastname: Wang
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Peter D
authors.initials: PD
authors.lastname: Aplan
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; C093350:nuclear pore complex protein 98; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse; D004221:Disulfiram