title: Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia.
abstract: Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA; Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
authors.forename: Kaiwei
authors.initials: K
authors.lastname: Liang
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA; Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, 303 E. Superior St., Chicago, IL 60611, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Volk
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Haug
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA.
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Marshall
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Woodfin
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Bartom
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Gilmore
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66150, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.affiliation: Linda Crnic Institute for Down Syndrome & Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Sullivan
authors.affiliation: Linda Crnic Institute for Down Syndrome & Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Joaquin M
authors.initials: JM
authors.lastname: Espinosa
authors.affiliation: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Pathology, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cannova
authors.affiliation: Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA; Department of Pathology, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA; Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, 303 E. Superior St., Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, Il 60611, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA; Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, Il 60611, USA. Electronic address: ash@northwestern.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D044763:Ubiquitin-Conjugating Enzymes
chemical_list: D007375:Interleukin-1; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; C000589772:UBE2O protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: IRAK1; IRAK4; MLL; MLL chimera; SEC; UBE2O; interleukin-1; mixed-lineage leukemia; super elongation complex; wild-type MLL