title: CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis.
abstract: Chromosomal translocations involving the mixed lineage leukemia (MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Tan
authors.forename: Morgan
authors.initials: M
authors.lastname: Jones
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Manabu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Muntean
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006410:Hematopoiesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology; D017354:Point Mutation; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D025941:Protein Interaction Mapping; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016415:Sequence Alignment; D014178:Translocation, Genetic
chemical_list: C570428:CBX8 protein, human; D018398:Homeodomain Proteins; C474558:MLL-AF9 fusion protein, human; C551356:MLL-AF9 fusion protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D015514:Oncogene Proteins, Fusion; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C570429:Cbx8 protein, mouse; D063150:Polycomb Repressive Complex 1
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