title: Transcription control by the ENL YEATS domain in acute leukaemia.
abstract: Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Erb
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Scott
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bin E
authors.initials: BE
authors.lastname: Li
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Joshiawa
authors.initials: J
authors.lastname: Paulk
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Hyuk-Soo
authors.initials: HS
authors.lastname: Seo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Souza
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Roberts
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Shiva
authors.initials: S
authors.lastname: Dastjerdi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Buckley
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.|McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Neville E
authors.initials: NE
authors.lastname: Sanjana
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.|McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Ophir
authors.initials: O
authors.lastname: Shalem
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Behnam
authors.initials: B
authors.lastname: Nabet
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Rhamy
authors.initials: R
authors.lastname: Zeid
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Nana K
authors.initials: NK
authors.lastname: Offei-Addo
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.|McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Georg E
authors.initials: GE
authors.lastname: Winter
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D000072669:Gene Editing; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000072417:Protein Domains; D059748:Proteolysis; D012319:RNA Polymerase II / Q000378:metabolism; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C090862:ELL protein, human; C497422:KMT2A protein, human; C493508:Mllt1 protein, mouse; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II