title: NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis.
abstract: The nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here, we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. Chromatin immunoprecipitation sequencing illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with Hox gene promoter regions. Furthermore, MLL1 is required for the proliferation of NHA9 cells in vitro and in vivo. Inactivation of MLL1 leads to decreased expression of genes bound by NHA9 and MLL1 and reverses a gene expression signature found in NUP98-rearranged human leukemias. Our data reveal a molecular dependency on MLL1 function in NUP98-fusion-driven leukemogenesis.
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: haiming_xu@dfci.harvard.edu.
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Daria G
authors.initials: DG
authors.lastname: Valerio
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Eisold
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Koche
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Wenhuo
authors.initials: W
authors.lastname: Hu
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: S Haihua
authors.initials: SH
authors.lastname: Chu
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Gerard L
authors.initials: GL
authors.lastname: Brien
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: scott_armstrong@dfci.harvard.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; C093350:nuclear pore complex protein 98; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
keywords: Hox gene; NUP98 fusion; leukemia; mixed lineage leukemia 1; non-specific lethal histone-modifying complexes