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

The adapter protein Slp65 is a key component of the precursor-B (pre-B) cell receptor. Slp65-deficientmicespontaneouslydevelop 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 developmentinBtk/Slp65/mice.Thisfinding paralleled the reported effect of a human immunoglobulin heavy chain transgene on lymphoma development in E-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 preB cells very efficiently.Aberrations in p19Arf, Mdm2, or p53 expression were found in all Slp65/(n 17)andBtk/Slp65/(n 32) pre-B cell leukemias analyzed. In addition, 9o f 10 p53/Slp65/ pre-B cell leukemias manifestedsignificantMdm2proteinexpression. These data indicate that malignant transformation of Slp65/ pre-B cells involves disruption of the p19Arf-Mdm2-p53 tumor suppressor pathway. (Blood. 2010; 115:1385-1393)