title: MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.
abstract: Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.
authors.affiliation: Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Rappaport
authors.affiliation: Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kitzing
authors.affiliation: Computational Biology Center, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Aditya S
authors.initials: AS
authors.lastname: Shroff
authors.affiliation: Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02215, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: LeBeau
authors.affiliation: Department of Pediatrics, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shannon
authors.affiliation: Department of Laboratory Medicine & Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kogan
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA; Research Institute of Molecular Pathology, 1030 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D057895:Haploinsufficiency / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D014230:Triazoles / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins
chemical_list: D001381:Azepines; D011495:Histone-Lysine N-Methyltransferase; D051788:Myeloid-Lymphoid Leukemia Protein; D034741:RNA, Small Interfering; D014230:Triazoles; D025521:Tumor Suppressor Proteins; C561695:(+)-JQ1 compound; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins