PROTEIN-KINASE A-DEPENDENT TRANSACTIVATION BY THE E2A-PBX1 FUSION PROTEIN

The chimeric gene E2A-PBX1 is formed by the t(1;19) chromosomal transl ocation exclusively associated with pediatric pre-B cell acute lymphob lastic leukemia (pre-B ALL). The resultant fusion protein from this ch imeric gene contains the DNA-binding homeodomain of Pbx1. The first an d only functional Pbx1 binding site has been localized in bovine CYP17 to a sequence (CRS1) that participates in cAMP-dependent transcriptio n of this gene encoding the steroid hydroxylase, 17 alpha-hydroxylase cytochrome P450. Because Pbx1 is not expressed in pre-B cells, it may be possible that the E2a-Pbx1 fusion protein expressed in pre-B cells having this translocation will activate, in response to cAMP, transcri ption of genes not normally expressed in these cells leading to arrest of differentiation at the pre-B cell stage. We have now shown that re porter genes comprising CRS1 are activated transcriptionally by protei n kinase A (PKA) in the pre-B cell line 697, which endogenously expres ses the fusion protein, and that overexpression of E2A-Pbx1 in additio nal cell lines enhances transcription of reporter genes in a PKA-depen dent fashion. Thus, it seems plausible that arrest in the pre-B stage leading to pre-B ALL includes cAMP-dependent activation of E2A-Pbx1.