BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias.

TLDR

The c‑abl proto‑oncogene encodes a cytoplasmic tyrosine kinase homologous to src, and loss of its SH3 domain in the murine v‑abl oncogene enables transformation when combined with N‑terminal myristylation, whereas the human BCR/ABL fusion retains an intact SH3 domain and lacks N‑terminal myristylation. To analyze the contribution of BCR‑encoded sequences to BCR/ABL‑mediated transformation, the authors performed deletion and substitution experiments in fibroblast and hematopoietic‑cell transformation assays. The authors assessed the effects of a series of deletions and substitutions in these assays to determine how BCR‑encoded sequences influence BCR/ABL transformation. BCR first‑exon sequences specifically potentiate transformation and tyrosine‑kinase activation when fused to the second exon of intact c‑ABL, indicating that BCR‑encoded sequences disrupt negative regulation of ABL and represent a novel activation mechanism for non‑receptor tyrosine‑kinase proto‑oncogenes.

Abstract

The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.