title: Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells.
abstract: Mixed Lineage Leukemia (MLL1) translocations encode fusion proteins retaining the N terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis and thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs); therefore, disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B cells, menin- or MLL1-regulated genes can be classified into 3 categories: (1) a relatively small group of coregulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of (2) exclusively menin-regulated and (3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these 2 proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1-disrupting drugs as safe and selective leukemia targeting agents.
authors.affiliation: Department of Genetics and Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH;
authors.forename: Bin E
authors.initials: BE
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Gan
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Terence H
authors.initials: TH
authors.lastname: Rabbitts
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D004843:Epistasis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein
references.citation: Nature. 1995 Nov 30;378(6556):505-8
references.pmid: 7477409
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12000-5
references.pmid: 23744037
references.citation: Nature. 2009 Mar 26;458(7237):529-33
references.pmid: 19212323
references.citation: Epigenetics Chromatin. 2009 Apr 06;2(1):5
references.pmid: 19348672
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1018-23
references.pmid: 16415155
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1118-23
references.pmid: 11158604
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):749-54
references.pmid: 15640349
references.citation: Mech Dev. 2009 Jul;126(7):517-22
references.pmid: 19393316
references.citation: Biomed Pharmacother. 2000 Jun;54 Suppl 1:187s-190s
references.pmid: 10915021
references.citation: J Biol Chem. 2011 Sep 9;286(36):31742-8
references.pmid: 21757704
references.citation: Blood. 2011 Jun 23;117(25):6895-905
references.pmid: 21518926
references.citation: Mamm Genome. 2004 Nov;15(11):872-7
references.pmid: 15672591
references.citation: PLoS Genet. 2006 Apr;2(4):e51
references.pmid: 16604156
references.citation: Nat Rev Cancer. 2007 Nov;7(11):823-33
references.pmid: 17957188
references.citation: Blood. 2011 May 12;117(19):5057-66
references.pmid: 21343612
references.citation: Dev Cell. 2004 Mar;6(3):437-43
references.pmid: 15030765
references.citation: Science. 1997 Apr 18;276(5311):404-7
references.pmid: 9103196
references.citation: Cancer Cell. 2008 Jul 8;14(1):36-46
references.pmid: 18598942
references.citation: Nature. 2012 Feb 12;482(7386):542-6
references.pmid: 22327296
references.citation: Blood. 2009 Feb 19;113(8):1661-9
references.pmid: 19228930
references.citation: Cell Stem Cell. 2012 Sep 7;11(3):302-17
references.pmid: 22958929
references.citation: Mol Cell. 2004 Feb 27;13(4):587-97
references.pmid: 14992727
references.citation: Cancer Res. 2003 Jul 15;63(14):4204-10
references.pmid: 12874027
references.citation: Mol Cell. 2002 Nov;10(5):1119-28
references.pmid: 12453419
references.citation: Mol Cell Biol. 2004 Jul;24(13):5639-49
references.pmid: 15199122
references.citation: Mol Cell. 2002 Nov;10(5):1107-17
references.pmid: 12453418
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3837-42
references.pmid: 11274402
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):324-37
references.pmid: 18371366
references.citation: PLoS One. 2012;7(5):e37952
references.pmid: 22666422
references.citation: Cancer Res. 2006 Sep 1;66(17):8397-403
references.pmid: 16951149
references.citation: Genes Dev. 2011 Apr 1;25(7):661-72
references.pmid: 21460034
references.citation: Cancer Res. 2007 Aug 1;67(15):7275-83
references.pmid: 17671196
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):338-45
references.pmid: 18371367
references.citation: Oncogene. 2001 Aug 16;20(36):4917-25
references.pmid: 11526476
references.citation: Nat Rev Mol Cell Biol. 2011 Nov 23;12(12):799-814
references.pmid: 22108599
references.citation: Mol Cell Biol. 2003 Dec;23(24):9003-13
references.pmid: 14645513
references.citation: Cancer Genet Cytogenet. 1991 Mar;52(1):85-92
references.pmid: 1672620
references.citation: J Exp Med. 1991 May 1;173(5):1213-25
references.pmid: 1827140
references.citation: Cell. 2005 Oct 21;123(2):207-18
references.pmid: 16239140
references.citation: Mol Cell Biol. 2003 Sep;23(17):6075-85
references.pmid: 12917331
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14659-64
references.pmid: 16195383
references.citation: Nat Chem Biol. 2012 Jan 29;8(3):277-84
references.pmid: 22286128
references.citation: Immunity. 2006 May;24(5):611-22
references.pmid: 16713978
references.citation: Curr Biol. 2004 Nov 23;14(22):2063-9
references.pmid: 15556871
references.citation: Blood. 2007 Feb 15;109(4):1472-8
references.pmid: 17047146
references.citation: Immunity. 2012 Apr 20;36(4):572-85
references.pmid: 22483804
references.citation: Leukemia. 2010 Oct;24(10):1732-41
references.pmid: 20724987
references.citation: Oncogene. 2010 Sep 9;29(36):5019-31
references.pmid: 20581860
references.citation: Cell. 1999 Jan 8;96(1):143-52
references.pmid: 9989505
references.citation: Nat Cell Biol. 2010 Oct;12(10):999-1006
references.pmid: 20835244