title: Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia.
abstract: MLL1, located on human chromosome 11, is disrupted in distinct recurrent chromosomal translocations in several leukemia subsets. Studying the MLL1 gene and its oncogenic variants has provided a paradigm for understanding cancer initiation and maintenance through aberrant epigenetic gene regulation. Here we review the historical development of model systems to recapitulate oncogenic MLL1-rearrangement (MLL-r) alleles encoding mixed-lineage leukemia fusion proteins (MLL-FPs) or internal gene rearrangement products. These largely mouse and human cell/xenograft systems have been generated and used to understand how MLL-r alleles affect diverse pathways to result in a highly penetrant, drug-resistant leukemia. The particular features of the animal models influenced the conclusions of mechanisms of transformation. We discuss significant downstream enablers, inhibitors, effectors, and collaborators of MLL-r leukemia, including molecules that directly interact with MLL-FPs and endogenous mixed-lineage leukemia protein, direct target genes of MLL-FPs, and other pathways that have proven to be influential in supporting or suppressing the leukemogenic activity of MLL-FPs. The use of animal models has been complemented with patient sample, genome-wide analyses to delineate the important genomic and epigenomic changes that occur in distinct subsets of MLL-r leukemia. Collectively, these studies have resulted in rapid progress toward developing new strategies for targeting MLL-r leukemia and general cell-biological principles that may broadly inform targeting aberrant epigenetic regulators in other cancers.
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Bin E
authors.initials: BE
authors.lastname: Li
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Department of Pediatrics Hematology/Oncology/BMT, University of Colorado Anschutz Medical Center, Aurora, CO, USA. Electronic address: patricia.ernst@ucdenver.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D055879:Gene Knock-In Techniques; D064593:Heterografts; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D007942:Leukemia, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D046912:Multiprotein Complexes; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse