title: Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress.
abstract: Understanding the critical factors that govern recovery of the hematopoietic system from stress, such as during anticancer therapy and bone marrow transplantation, is of clinical significance. We investigated the importance of the prosurvival proteins myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma-extra large (BCL-XL) in stem/progenitor cell survival and fitness during hematopoietic recovery from stress. Loss of a single Mcl-1 allele, which reduced MCL-1 protein levels, severely compromised hematopoietic recovery from myeloablative challenge and following bone marrow transplantation, whereas BCL-XL was dispensable in both contexts. We identified inhibition of proapoptotic p53 upregulated modulator of apoptosis (PUMA) as the key role of MCL-1 in both settings, with Mcl-1(+/-);Puma(-/-) mice completely protected from the deleterious effects of loss of 1 Mcl-1 allele. These results reveal the molecular mechanisms that govern cell survival during hematopoietic recovery from stress.
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia; and.
authors.forename: Alex R D
authors.initials: AR
authors.lastname: Delbridge
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia; and.
authors.forename: Stephanie
authors.identifier: http://orcid.org/0000-0003-0467-7871
authors.initials: S
authors.lastname: Grabow
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002469:Cell Separation; D002470:Cell Survival / Q000502:physiology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D013312:Stress, Physiological; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C488588:PUMA protein, mouse; D025521:Tumor Suppressor Proteins
references.citation: Science. 1999 Nov 26;286(5445):1735-8
references.pmid: 10576740
references.citation: West J Med. 2000 Apr;172(4):248-52
references.pmid: 10778379
references.citation: Annu Rev Biochem. 2000;69:217-45
references.pmid: 10966458
references.citation: Annu Rev Immunol. 2003;21:759-806
references.pmid: 12615892
references.citation: Cancer Cell. 2003 Oct;4(4):321-8
references.pmid: 14585359
references.citation: Science. 2003 Nov 7;302(5647):1036-8
references.pmid: 14500851
references.citation: Nature. 2003 Dec 11;426(6967):671-6
references.pmid: 14668867
references.citation: Cell. 1991 Nov 29;67(5):889-99
references.pmid: 1959134
references.citation: Science. 1995 Mar 10;267(5203):1506-10
references.pmid: 7878471
references.citation: Cancer Res. 1960 May;20:497-502
references.pmid: 14417173
references.citation: Mol Cell. 2005 Feb 4;17(3):393-403
references.pmid: 15694340
references.citation: Science. 2005 Feb 18;307(5712):1101-4
references.pmid: 15718471
references.citation: Blood. 2005 Dec 15;106(13):4131-8
references.pmid: 16118324
references.citation: Bone Marrow Transplant. 2006 Sep;38(5):377-84
references.pmid: 16915226
references.citation: Blood. 2007 Feb 15;109(4):1620-6
references.pmid: 17062731
references.citation: Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59
references.pmid: 18097445
references.citation: Blood. 2009 Mar 19;113(12):2805-15
references.pmid: 19064728
references.citation: Blood. 2010 Apr 29;115(17):3472-80
references.pmid: 20177048
references.citation: Blood. 2010 Jun 10;115(23):4707-14
references.pmid: 20360471
references.citation: Genes Dev. 2010 Aug 1;24(15):1602-7
references.pmid: 20679395
references.citation: Genes Dev. 2010 Aug 1;24(15):1608-13
references.pmid: 20679396
references.citation: Science. 2010 Nov 19;330(6007):1095-9
references.pmid: 20929728
references.citation: Genes Dev. 2012 Jan 15;26(2):120-5
references.pmid: 22279045
references.citation: Cold Spring Harb Perspect Biol. 2012 Dec;4(12). pii: a008250. doi: 10.1101/cshperspect.a008250
references.pmid: 23209149
references.citation: EMBO Mol Med. 2013 Jan;5(1):122-36
references.pmid: 23180554
references.citation: Nat Rev Mol Cell Biol. 2014 Jan;15(1):49-63
references.pmid: 24355989
references.citation: Genes Dev. 2014 Jan 1;28(1):58-70
references.pmid: 24395247
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):261-6
references.pmid: 24363325