THE V-ABL TYROSINE KINASE NEGATIVELY REGULATES NF-KAPPA-B REL FACTORS AND BLOCKS KAPPA-GENE TRANSCRIPTION IN PRE-B-LYMPHOCYTES

Transformation of B-lineage precursors by the Abelson murine leukemia virus appears to arrest development at the pre-B stage. Abelson-transformed pre-B cell lines generally retain transcriptionally inactive, unrearranged immunoglobulin kappa alleles. We demonstrate that nontransformed pre-B cells expanded from the mouse bone marrow efficiently transcribe unrearranged kappa alleles. In addition, they contain activated complexes of the NF-kappaB/Rel transcription factor family, in contrast with their Abelson-transformed counterparts. Using conditionally transformed pre-B cell lines, we show that the v-abl viral transforming protein, a tyrosine kinase, blocks germ-line kappa gene transcription and negatively regulates NF-kappaB/Rel activity. An active v-abl kinase specifically inhibits the NF-kappaB/Rel-dependent kappaK intron enhancer, which is implicated in promoting both transcription and rearrangement of the kappa locus. v-abl inhibits the activated state of NF-kappaB/Rel complexes in a pre-B cell via a post-translational mechanism that results in increased stability of the inhibitory subunit IkappaBalpha. This analysis suggests a molecular pathway by which v-abl inhibits kappa locus transcription and rearrangement.