C/EBPb cooperates with BLNK mutation in preB leukemogenesis (BLNK2)

BLNK (BASH/SLP-65) encodes an adaptor protein within the B-cell receptor signaling. Loss-of-function mutations of BLNK are observed in human preB-ALL, and a subset of Blnk knock-out mice develop preB-ALL. To understand the molecular mechanism of preB-ALL development associated with the Blnk mutation, retroviral tagging was applied on Blnk KO mice using Moloney murine leukemia virus (MoMLV). The Blnk mutation significantly accelerated the disease onset of MoMLV-induced leukemia and increased the incidence of preB-ALL. Cebpb was identified as the most frequent common retroviral integration site, suggesting that Cebpb upregulation cooperates with Blnk mutation. Transgenic expression of the LAP (liver-enriched activator protein) isoform of C/EBP-beta significantly accelerated preB-ALL development of Blnk ko mice. We used microarrays to detail the global program of gene expression in mouse preB-ALL Murine preB-ALL cell line LB31 and non-neoplastic bone marrow B-lymphocytes derived from wild type, Blnk KO, Cebpb LAP transgenic and Blnk KO/LAP tg mice were examined.