title: Self-renewal of leukemia stem cells in Friend virus-induced erythroleukemia requires proviral insertional activation of Spi1 and hedgehog signaling but not mutation of p53.
abstract: Friend virus induces erythroleukemia through a characteristic two-stage progression. The prevailing model proposes that during the initial, polyclonal stage of disease most of the infected cells terminally differentiate, resulting in acute erythrocytosis. In the late stage of disease, a clonal leukemia develops through the acquisition of new mutations--proviral insertional activation of Spi1/Pu.1 and mutation of p53. Previous work from our laboratory demonstrated that Friend virus activates the bone morphogenic protein 4 (BMP4)-dependent stress erythropoiesis pathway, which leads to the rapid expansion of stress erythroid progenitors, which are the targets for Friend virus in the spleen. We recently showed that stress erythroid progenitors have intrinsic self-renewal ability and therefore could function as leukemia stem cells (LSCs) when infected with Friend virus. Here, we show that the two stages of Friend virus-induced disease are caused by infection of distinct stress progenitor populations in the spleen. The development of leukemia relies on the ability of the virus to hijack the intrinsic self-renewal capability of stress erythroid progenitors leading to the generation of LSCs. Two signals are required for the self-renewal of Friend virus LSCs proviral insertional activation of Spi1/Pu.1 and Hedgehog-dependent signaling. Surprisingly, mutation of p53 is not observed in LSCs. These data establish a new model for Friend virus-induced erythroleukemia and demonstrate the utility of Friend virus as a model system to study LSC self-renewal.
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Hegde
authors.forename: Pamela
authors.initials: P
authors.lastname: Hankey
authors.forename: Robert F
authors.initials: RF
authors.lastname: Paulson
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005622:Friend murine leukemia virus / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology* / Q000821:virology; D007942:Leukemia, Experimental / Q000473:pathology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011086:Polycythemia; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011533:Proviruses; D012192:Retroviridae Infections / Q000473:pathology* / Q000821:virology; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014412:Tumor Virus Infections / Q000473:pathology* / Q000821:virology; D014759:Viral Envelope Proteins / Q000378:metabolism; D016662:Virus Integration; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D053823:Hedgehog Proteins; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014759:Viral Envelope Proteins; D000099232:Proto-Oncogene Protein Spi-1
references.citation: Genes Dev. 1994 Nov 1;8(21):2540-51
references.pmid: 7958916
references.citation: Cancer Cell. 2008 Sep 9;14(3):238-49
references.pmid: 18772113
references.citation: Oncogene. 1998 Jun 11;16(23):2989-95
references.pmid: 9662331
references.citation: Blood. 2004 May 15;103(10):3615-23
references.pmid: 14739214
references.citation: Blood. 2004 Dec 15;104(13):3894-900
references.pmid: 15328162
references.citation: Virology. 1981 Jan 30;108(2):309-17
references.pmid: 6936971
references.citation: J Biol Chem. 2010 Jan 29;285(5):3044-52
references.pmid: 19955566
references.citation: Cancer Cell. 2004 Dec;6(6):587-96
references.pmid: 15607963
references.citation: Mol Cell Biol. 1990 Jul;10(7):3307-13
references.pmid: 1694008
references.citation: J Clin Invest. 2010 Dec;120(12):4507-19
references.pmid: 21060151
references.citation: Oncogene. 2002 May 16;21(22):3562-70
references.pmid: 12032858
references.citation: Nature. 1985 Apr 18-24;314(6012):633-6
references.pmid: 3990796
references.citation: J Virol. 2005 Dec;79(23):14586-94
references.pmid: 16282458
references.citation: Genes Funct. 1997 Feb;1(1):69-83
references.pmid: 9680329
references.citation: Leukemia. 1990 Jan;4(1):20-3
references.pmid: 2153262
references.citation: Cancer Cell. 2005 Dec;8(6):467-78
references.pmid: 16338660
references.citation: Virology. 1983 May;127(1):134-48
references.pmid: 6305011
references.citation: Oncogene. 1988 Aug;3(2):179-85
references.pmid: 2842714
references.citation: Nature. 1978 Nov 30;276(5687):506-8
references.pmid: 723932
references.citation: J Virol. 2008 Jan;82(1):382-93
references.pmid: 17942544
references.citation: Trends Cell Biol. 2005 Sep;15(9):494-501
references.pmid: 16084092
references.citation: Cell. 1991 Sep 6;66(5):831-4
references.pmid: 1889087
references.citation: Cell. 1980 Dec;22(3):693-9
references.pmid: 6936081
references.citation: Nature. 2004 Mar 18;428(6980):337-41
references.pmid: 15029199
references.citation: Leuk Res. 2005 Aug;29(8):933-42
references.pmid: 15978944
references.citation: Science. 2002 Aug 30;297(5586):1559-61
references.pmid: 12202832
references.citation: Nature. 1988 Jan 21;331(6153):277-80
references.pmid: 2827041
references.citation: Nature. 2009 Apr 9;458(7239):776-9
references.pmid: 19169242
references.citation: Genes Dev. 1999 Jun 1;13(11):1398-411
references.pmid: 10364157
references.citation: Blood. 2000 Oct 15;96(8):2641-8
references.pmid: 11023493
references.citation: Proc Soc Exp Biol Med. 1961 Aug-Sep;107:824-8
references.pmid: 14474419
references.citation: Proc Natl Acad Sci U S A. 1981 Mar;78(3):1703-7
references.pmid: 6940184
references.citation: Cell. 2009 Sep 18;138(6):1083-95
references.pmid: 19766563
references.citation: Cell Stem Cell. 2007 Jun 7;1(1):113-26
references.pmid: 18371340
references.citation: Cancer Res. 2006 Jun 15;66(12):6063-71
references.pmid: 16778178
references.citation: Nat Genet. 1999 Oct;23(2):159-65
references.pmid: 10508511
references.citation: Stem Cells Dev. 2009 Oct;18(8):1127-34
references.pmid: 19409053
references.citation: Nature. 1994 Feb 17;367(6464):645-8
references.pmid: 7509044
references.citation: Proc Soc Exp Biol Med. 1973 Feb;142(2):538-41
references.pmid: 4689386
references.citation: Dev Biol. 2008 May 1;317(1):24-35
references.pmid: 18374325
references.citation: Retrovirology. 2008 Nov 04;5:99
references.pmid: 18983647
references.citation: Oncogene. 2009 Sep 24;28(38):3349-59
references.pmid: 19581930
references.citation: Biol Blood Marrow Transplant. 2005 Feb;11(2 Suppl 2):9-11
references.pmid: 15682167
references.citation: Cell. 1979 Sep;18(1):145-52
references.pmid: 509518
references.citation: Blood. 2005 Sep 1;106(5):1590-600
references.pmid: 15914556
references.citation: Curr Opin Immunol. 2010 Apr;22(2):177-84
references.pmid: 20207529
references.citation: Blood. 2007 May 15;109(10):4494-502
references.pmid: 17284534
references.citation: Cell. 2006 Aug 25;126(4):755-66
references.pmid: 16923394