title: Malignant transformation of Slp65-deficient pre-B cells involves disruption of the Arf-Mdm2-p53 tumor suppressor pathway.
abstract: The adapter protein Slp65 is a key component of the precursor-B (pre-B) cell receptor. Slp65-deficient mice spontaneously develop pre-B cell leukemia, but the mechanism by which Slp65(-/-) pre-B cells become malignant is unknown. Loss of Btk, a Tec-family kinase that cooperates with Slp65 as a tumor suppressor, synergizes with deregulation of the c-Myc oncogene during lymphoma formation. Here, we report that the presence of the immunoglobulin heavy chain transgene V(H)81X prevented tumor development in Btk(-/-)Slp65(-/-) mice. This finding paralleled the reported effect of a human immunoglobulin heavy chain transgene on lymphoma development in Emu-myc mice, expressing transgenic c-Myc. Because activation of c-Myc strongly selects for spontaneous inactivation of the p19(Arf)-Mdm2-p53 tumor suppressor pathway, we investigated whether disruption of this pathway is a common alteration in Slp65(-/-) pre-B cell tumors. We found that combined loss of Slp65 and p53 in mice transformed pre-B cells very efficiently. Aberrations in p19(Arf), Mdm2, or p53 expression were found in all Slp65(-/-) (n = 17) and Btk(-/-)Slp65(-/-) (n = 32) pre-B cell leukemias analyzed. In addition, 9 of 10 p53(-/-)Slp65(-/-) pre-B cell leukemias manifested significant Mdm2 protein expression. These data indicate that malignant transformation of Slp65(-/-) pre-B cells involves disruption of the p19(Arf)-Mdm2-p53 tumor suppressor pathway.
authors.affiliation: Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
authors.forename: Van B T
authors.initials: VB
authors.lastname: Ta
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.forename: Petra J
authors.initials: PJ
authors.lastname: ter Brugge
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.forename: Hans J A
authors.initials: HJ
authors.lastname: Diepstraten
authors.forename: Pieter Fokko
authors.initials: PF
authors.lastname: van Loo
authors.forename: Rogier
authors.initials: R
authors.lastname: Kersseboom
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D033481:Chromosomes, Mammalian; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D054448:Precursor Cells, B-Lymphoid / Q000473:pathology / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D019076:Transgenes / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D003564:Cytidine Deaminase