Malignant transformation of Slp65-deficient pre-B cells involves disruption of the Arf-Mdm2-p53 tumor suppressor pathway

Abstract

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 VH81X prevented tumor development in Btk−/−Slp65−/− mice. This finding paralleled the reported effect of a human immunoglobulin heavy chain transgene on lymphoma development in Eμ-myc mice, expressing transgenic c-Myc. Because activation of c-Myc strongly selects for spontaneous inactivation of the p19Arf-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 p19Arf, 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 p19Arf-Mdm2-p53 tumor suppressor pathway.