title: Rapidly fatal myeloproliferative disorders in mice with deletion of Casitas B-cell lymphoma (Cbl) and Cbl-b in hematopoietic stem cells.
abstract: Casitas B-cell lymphoma (Cbl)-family E3 ubiquitin ligases are negative regulators of tyrosine kinase signaling. Recent work has revealed a critical role of Cbl in the maintenance of hematopoietic stem cell (HSC) homeostasis, and mutations in CBL have been identified in myeloid malignancies. Here we show that, in contrast to Cbl or Cbl-b single-deficient mice, concurrent loss of Cbl and Cbl-b in the HSC compartment leads to an early-onset lethal myeloproliferative disease in mice. Cbl, Cbl-b double-deficient bone marrow cells are hypersensitive to cytokines, and show altered biochemical response to thrombopoietin. Thus, Cbl and Cbl-b play redundant but essential roles in HSC regulation, whose breakdown leads to hematological abnormalities that phenocopy crucial aspects of mutant Cbl-driven human myeloid malignancies.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases and Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA. mnaramura@unmc.edu
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
authors.forename: Neha
authors.initials: N
authors.lastname: Nandwani
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000375:Aging; D000818:Animals; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000378:metabolism*; D013926:Thrombopoietin / Q000378:metabolism; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D013926:Thrombopoietin; D050721:Proto-Oncogene Proteins c-cbl
references.citation: PLoS One. 2008;3(11):e3776
references.pmid: 19020663
references.citation: Cell. 2004 Jul 23;118(2):217-28
references.pmid: 15260991
references.citation: Cancer Res. 2008 Dec 15;68(24):10349-57
references.pmid: 19074904
references.citation: Nature. 2009 Aug 13;460(7257):904-8
references.pmid: 19620960
references.citation: Haematologica. 2008 Oct;93(10):1595-7
references.pmid: 18698078
references.citation: EMBO J. 2005 Nov 2;24(21):3807-19
references.pmid: 16211006
references.citation: Blood. 2007 Aug 1;110(3):1004-12
references.pmid: 17446348
references.citation: Blood. 2009 Aug 27;114(9):1859-63
references.pmid: 19571318
references.citation: Nat Immunol. 2002 Dec;3(12):1192-9
references.pmid: 12415267
references.citation: Curr Opin Genet Dev. 2009 Oct;19(5):461-8
references.pmid: 19811902
references.citation: Blood. 2002 Jul 1;100(1):238-45
references.pmid: 12070033
references.citation: J Exp Med. 2003 Feb 17;197(4):503-13
references.pmid: 12591907
references.citation: Blood. 2009 Jun 11;113(24):6182-92
references.pmid: 19387008
references.citation: Immunity. 2004 Jul;21(1):7-17
references.pmid: 15345216
references.citation: Clin Cancer Res. 2009 Apr 1;15(7):2238-47
references.pmid: 19276253
references.citation: Nature. 2000 Jan 13;403(6766):216-20
references.pmid: 10646609
references.citation: Blood. 2007 Aug 1;110(3):1022-4
references.pmid: 17475912
references.citation: Blood. 2009 Nov 5;114(19):4197-208
references.pmid: 19734451
references.citation: Blood. 2009 Apr 30;113(18):4414-24
references.pmid: 19179468
references.citation: Mol Cell Biol. 1998 Aug;18(8):4872-82
references.pmid: 9671496
references.citation: Nat Rev Mol Cell Biol. 2005 Dec;6(12):907-18
references.pmid: 16227975
references.citation: Genes Dev. 2008 Apr 15;22(8):992-7
references.pmid: 18413713
references.citation: Transgenic Res. 2001 Dec;10(6):545-53
references.pmid: 11817542
references.citation: J Clin Oncol. 2009 Dec 20;27(36):6109-16
references.pmid: 19901108
references.citation: Nat Rev Mol Cell Biol. 2001 Apr;2(4):294-307
references.pmid: 11283727
references.citation: Blood. 2007 May 1;109(9):3945-52
references.pmid: 17192389
references.citation: J Biol Chem. 2010 Apr 2;285(14):10969-81
references.pmid: 20133944
references.citation: Stem Cells. 2009 Jan;27(1):175-82
references.pmid: 18927475
references.citation: FEBS Lett. 2000 Mar 31;470(3):263-8
references.pmid: 10745079
references.citation: J Clin Invest. 2007 Apr;117(4):1029-36
references.pmid: 17364027
references.citation: Cell Stem Cell. 2007 Dec 13;1(6):685-97
references.pmid: 18371409
references.citation: Cancer Cell. 2008 Oct 7;14(4):335-43
references.pmid: 18835035
references.citation: Leukemia. 2008 Jul;22(7):1335-42
references.pmid: 18548091
references.citation: Blood. 2010 Feb 11;115(6):1254-63
references.pmid: 19880496
references.citation: Cell Stem Cell. 2007 Dec 13;1(6):671-84
references.pmid: 18371408
references.citation: Blood. 1991 Mar 1;77(5):925-9
references.pmid: 1704804
references.citation: J Exp Med. 2007 Apr 16;204(4):879-91
references.pmid: 17403934
references.citation: Blood. 2010 Mar 11;115(10):1969-75
references.pmid: 20008299
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15547-52
references.pmid: 9861006
references.citation: Mol Cell Biol. 2008 May;28(9):3020-37
references.pmid: 18316398