title: The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein. Integrating the results of these interference RNA screens and additional gene expression data, we identified the transcription factor ZEB2 as a novel AML dependency. ZEB2 depletion impaired the proliferation of both human and mouse AML cells and resulted in aberrant differentiation of human AML cells. Mechanistically, we showed that ZEB2 transcriptionally represses genes that regulate myeloid differentiation, including genes involved in cell adhesion and migration. In addition, we found that epigenetic silencing of the miR-200 family microRNAs affects ZEB2 expression. Our results extend the role of ZEB2 beyond regulating epithelial-mesenchymal transition (EMT) and establish ZEB2 as a novel regulator of AML proliferation and differentiation.
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Cell Biology, Harvard Medical School, Boston, MA.
authors.forename: Hubo
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.|Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Brenton G
authors.initials: BG
authors.lastname: Mar
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Cell Biology, Harvard Medical School, Boston, MA.
authors.forename: Huadi
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.|Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Rishi V
authors.initials: RV
authors.lastname: Puram
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.|Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.|Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ebert
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Cell Biology, Harvard Medical School, Boston, MA.
authors.forename: David
authors.initials: D
authors.lastname: Pellman
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; C551356:MLL-AF9 fusion protein, mouse; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2