PMID- 25264566 OWN - NLM STAT- MEDLINE DCOM- 20150202 LR - 20240322 IS - 1873-2399 (Electronic) IS - 0301-472X (Print) IS - 0301-472X (Linking) VI - 42 IP - 12 DP - 2014 Dec TI - Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia. PG - 995-1012 LID - S0301-472X(14)00676-6 [pii] LID - 10.1016/j.exphem.2014.09.006 [doi] AB - 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. CI - Copyright (c) 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved. FAU - Li, Bin E AU - Li BE AD - Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. FAU - Ernst, Patricia AU - Ernst P AD - 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. LA - eng GR - P30 CA023108/CA/NCI NIH HHS/United States GR - R01 HL090036/HL/NHLBI NIH HHS/United States GR - HL090036/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20140928 PL - Netherlands TA - Exp Hematol JT - Experimental hematology JID - 0402313 RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (KMT2A protein, human) RN - 0 (Multiprotein Complexes) RN - 0 (Neoplasm Proteins) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Transcription Factors) RN - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - EC 2.1.1.43 (Kmt2a protein, mouse) SB - IM MH - Alleles MH - Animals MH - Cell Transformation, Neoplastic MH - Chromatin Assembly and Disassembly MH - *Epigenesis, Genetic MH - *Gene Expression Regulation, Leukemic MH - Gene Knock-In Techniques MH - Heterografts MH - Histone-Lysine N-Methyltransferase/chemistry/*genetics/physiology MH - Humans MH - Intracellular Signaling Peptides and Proteins/chemistry/physiology MH - Leukemia/*genetics/pathology MH - Leukemia, Experimental/*genetics/pathology MH - Mice MH - Multiprotein Complexes MH - Myeloid-Lymphoid Leukemia Protein/chemistry/*genetics/physiology MH - Neoplasm Proteins/chemistry/*genetics/physiology MH - Oncogene Proteins, Fusion/chemistry/genetics/physiology MH - Protein Interaction Mapping MH - Protein Structure, Tertiary MH - Signal Transduction MH - Transcription Factors/physiology PMC - PMC4307938 MID - NIHMS631817 EDAT- 2014/09/30 06:00 MHDA- 2015/02/03 06:00 PMCR- 2015/12/01 CRDT- 2014/09/30 06:00 PHST- 2014/08/20 00:00 [received] PHST- 2014/09/16 00:00 [accepted] PHST- 2014/09/30 06:00 [entrez] PHST- 2014/09/30 06:00 [pubmed] PHST- 2015/02/03 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - S0301-472X(14)00676-6 [pii] AID - 10.1016/j.exphem.2014.09.006 [doi] PST - ppublish SO - Exp Hematol. 2014 Dec;42(12):995-1012. doi: 10.1016/j.exphem.2014.09.006. Epub 2014 Sep 28.