title: Recent progress toward epigenetic therapies: the example of mixed lineage leukemia.
abstract: The importance of epigenetic gene regulatory mechanisms in normal and cancer development is increasingly evident. Genome-wide analyses have revealed the mutation, deletion, and dysregulated expression of chromatin-modifying enzymes in a number of cancers, including hematologic malignancies. Genome-wide studies of DNA methylation and histone modifications are beginning to reveal the landscape of cancer-specific chromatin patterns. In parallel, recent genetic loss-of-function studies in murine models are demonstrating functional involvement of chromatin-modifying enzymes in malignant cell proliferation and self-renewal. Paradoxically, the same chromatin modifiers can, depending on cancer type, be either hyperactive or inactivated. Increasingly, cross talk between epigenetic pathways is being identified. Leukemias carrying MLL rearrangements are quintessential cancers driven by dysregulated epigenetic mechanisms in which fusion proteins containing N-terminal sequences of MLL require few or perhaps no additional mutations to cause human leukemia. Here, we review how recent progress in the field of epigenetics opens potential mechanism-based therapeutic avenues.
authors: Center for Cancer and Blood Disorders, Children's Hospital Colorado, and Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO, USA.
authors: Tobias
authors: T
authors: Neff
authors: Scott A
authors: SA
authors: Armstrong
mesh_terms: D000818:Animals; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015321:Gene Rearrangement / Q000235:genetics; D055106:Genome-Wide Association Study; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
references: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6629-34
references: 16618927
references: Blood. 2012 Aug 2;120(5):1107-17
references: 22677129
references: Nature. 2011 Aug 03;478(7370):524-8
references: 21814200
references: Genes Dev. 2012 Dec 1;26(23):2604-20
references: 23166019
references: Science. 2010 Mar 26;327(5973):1650-3
references: 20339075
references: Blood. 2010 Jul 8;116(1):63-70
references: 20395419
references: Nat Rev Cancer. 2011 Sep 23;11(10):726-34
references: 21941284
references: Cell Res. 2011 Apr;21(4):564-78
references: 21423274
references: Cell. 2005 Apr 22;121(2):167-78
references: 15851025
references: Blood. 2013 Mar 28;121(13):2533-41
references: 23361907
references: Dev Cell. 2012 Jan 17;22(1):25-37
references: 22192413
references: Genetics. 1998 Oct;150(2):613-32
references: 9755194
references: Genes Dev. 2008 Dec 15;22(24):3403-8
references: 19141473
references: Dev Cell. 2004 Mar;6(3):437-43
references: 15030765
references: Genes Dev. 2007 May 15;21(10):1169-78
references: 17470536
references: Blood. 2007 Dec 15;110(13):4445-54
references: 17855633
references: Cell. 2011 Sep 16;146(6):904-17
references: 21889194
references: Cancer Cell. 2010 Jan 19;17(1):13-27
references: 20060365
references: PLoS Genet. 2012;8(6):e1002781
references: 22737091
references: Nat Rev Genet. 2012 Apr 03;13(5):343-57
references: 22473383
references: Cancer Cell. 2008 Jul 8;14(1):36-46
references: 18598942
references: Cell. 2009 Dec 24;139(7):1290-302
references: 20064375
references: Cancer Cell. 2011 Jul 12;20(1):66-78
references: 21741597
references: Mol Cell. 2010 Feb 12;37(3):429-37
references: 20159561
references: Blood. 2011 Sep 8;118(10):2849-56
references: 21765021
references: Cancer Cell. 2011 Jul 12;20(1):53-65
references: 21741596
references: Nature. 2008 Oct 30;455(7217):1205-9
references: 18806775
references: Nature. 2011 Jul 27;476(7360):298-303
references: 21796119
references: Blood. 2011 Jan 6;117(1):234-41
references: 20855866
references: Epigenetics. 2009 Aug 16;4(6):383-7
references: 19684477
references: Blood. 2006 Mar 1;107(5):2170-9
references: 16293602
references: Cell. 2010 Apr 2;141(1):69-80
references: 20371346
references: Nat Commun. 2012 Jan 10;3:623
references: 22233633
references: Trends Cell Biol. 2010 Nov;20(11):662-71
references: 20863703
references: Blood. 2011 May 5;117(18):4759-68
references: 21398221
references: Am J Hematol. 2012 Mar;87(3):245-50
references: 22190018
references: Cancer Cell. 2012 Apr 17;21(4):473-87
references: 22464800
references: Nature. 2012 Dec 6;492(7427):108-12
references: 23051747
references: Cancer Cell. 2010 Feb 17;17(2):198-212
references: 20153263
references: Mol Cell. 2010 Jun 25;38(6):853-63
references: 20541448
references: Nat Genet. 2010 Aug;42(8):665-7
references: 20601954
references: Nature. 2011 Oct 02;478(7370):529-33
references: 21964340
references: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17603-8
references: 23045699
references: Cell. 2009 Dec 24;139(7):1303-14
references: 20064376
references: Mol Cell. 2008 Nov 21;32(4):491-502
references: 19026780
references: Cancer Res. 2010 Dec 15;70(24):10234-42
references: 21159644
references: Proc Natl Acad Sci U S A. 2009 May 26;106(21):8513-8
references: 19433796
references: Blood. 2008 Dec 1;112(12):4690-3
references: 18796627
references: Mol Cell Biol. 2009 Nov;29(22):6074-85
references: 19703992
references: Blood. 2011 Dec 15;118(25):6553-61
references: 22042701
references: Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20980-5
references: 21078963
references: Oncogene. 2013 Feb 14;32(7):930-8
references: 22469984
references: Nat Chem Biol. 2012 Nov;8(11):890-6
references: 23023262
references: Nature. 2002 Oct 10;419(6907):624-9
references: 12374981
references: Genes Dev. 2007 May 1;21(9):1050-63
references: 17437993
references: Genes Dev. 2012 Jan 1;26(1):37-42
references: 22215809
references: Mol Cancer Ther. 2009 Jun;8(6):1579-88
references: 19509260
references: Blood. 2008 Apr 15;111(8):4329-37
references: 18272813
references: Cell. 2010 Jun 25;141(7):1183-94
references: 20541251
references: Br J Haematol. 2001 Mar;112(4):950-8
references: 11298590
references: Epigenetics Chromatin. 2011 Sep 05;4:16
references: 21892963
references: Nat Genet. 2009 May;41(5):521-3
references: 19330029
references: Curr Biol. 2002 Jun 25;12(12):1052-8
references: 12123582
references: Cell Stem Cell. 2009 Feb 6;4(2):129-40
references: 19200802
references: Science. 2012 Dec 14;338(6113):1465-9
references: 23239736
references: Leukemia. 2013 Apr;27(4):852-60
references: 23235717
references: Nature. 2011 Feb 10;470(7333):279-83
references: 21160473
references: Nat Commun. 2012;3:1288
references: 23250418
references: Cancer Cell. 2008 Nov 4;14(5):355-68
references: 18977325
references: Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5028-33
references: 22396593
references: Cancer Cell. 2010 Jun 15;17(6):609-21
references: 20541477
references: Genes Dev. 2012 Apr 1;26(7):651-6
references: 22431509
references: Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5
references: 23236167
references: Blood. 2009 Sep 17;114(12):2489-96
references: 19528532
references: Cancer Cell. 2010 Dec 14;18(6):606-18
references: 21156284
references: Science. 2010 Aug 6;329(5992):689-93
references: 20616235
references: EMBO J. 2004 Jan 14;23(1):138-49
references: 14685282
references: Cell. 2010 Oct 15;143(2):313-24
references: 20946988
references: Science. 2011 Jan 28;331(6016):435-9
references: 21163964
references: Genes Dev. 2012 Feb 15;26(4):344-9
references: 22345515
references: J Mol Biol. 2010 Jul 9;400(2):137-44
references: 20452361
references: Nature. 2010 Mar 11;464(7286):306-10
references: 20075857
references: Cell. 2005 Oct 21;123(2):207-18
references: 16239140
references: Mol Cell. 2012 Jan 27;45(2):255-62
references: 22196887
references: Nat Chem Biol. 2012 Jan 29;8(3):277-84
references: 22286128
references: Cell Stem Cell. 2012 Nov 2;11(5):649-62
references: 23122289
references: Blood. 2009 Sep 24;114(13):2733-43
references: 19638619
references: Mol Cell. 2011 Sep 2;43(5):798-810
references: 21884980
references: Blood. 2011 Jun 23;117(25):6912-22
references: 21521783
references: Cell. 2012 Jun 22;149(7):1447-60
references: 22704655
references: Mol Cell. 2008 Nov 21;32(4):503-18
references: 19026781
references: Nature. 2003 Nov 6;426(6962):78-83
references: 14603321
references: Annu Rev Biochem. 2012;81:65-95
references: 22663077
references: Nature. 2010 Jan 21;463(7279):360-3
references: 20054297
references: Cancer Cell. 2010 Jun 15;17(6):597-608
references: 20541704
references: Cancer Cell. 2011 Nov 15;20(5):563-75
references: 22094252
references: Nat Genet. 2010 Aug;42(8):722-6
references: 20601953
references: EMBO J. 2003 Oct 15;22(20):5323-35
references: 14532106
references: Leukemia. 2013 Apr;27(4):813-22
references: 23138183
references: Cancer Cell. 2010 Feb 17;17(2):148-59
references: 20159607