The oncogene BCR–ABL1 induces the synthesis of a splice variant of Bruton's tyrosine kinase (BTKp52) that hijacks full-length BTK and transforms B cells.

The oncogene BCR–ABL1 hijacks a B cell signaling protein by inducing the synthesis of a linker protein, according to Feldhahn and colleagues on page 1837. This study helps explain how BCR–ABL1 causes B cell leukemias in humans and identifies a potential new target for drug development.

Translocation events that combine unrelated chromosomal sequences are found in up to 65% of human acute leukemias. One such translocation event creates a chimeric protein between the signaling protein BCR and the tyrosine kinase ABL1. The BCR–ABL1 fusion allows precursor B cells to bypass survival signals from the pre-B cell receptor that are normally required for B cell survival. But exactly how BCR–ABL1 ensures B cell survival in the absence of pre-B cell receptor signals was not completely clear.

Feldhahn et al. now show that Bruton's tyrosine kinase (BTK)—a key component of the pre-B cell receptor signaling pathway—is perpetually phosphorylated (and thus activated) in BCR–ABL1-expressing leukemia cells. Downstream signals, including calcium flux and expression of the pro-survival protein Bcl-xL, were also activated in these cells. BTK phosphorylation depended on the kinase activity of BCR–ABL1, as inhibiting this kinase decreased BTK phosphorylation. But the mechanism was mysterious, as previous studies had ruled out a direct interaction between BCR–ABL1 and BTK.

The authors had noted that several kinase-deficient splice variants of BTK accumulated in leukemia cells. One of these variants (BTKp52) bound to both BCL–ABL1 and full-length BTK, providing a bridge that allowed BCR–ABL1 to phosphorylate full-length BTK. BTKp52 was needed to maintain cell survival, as removal of this protein drove the cells into apoptosis. Remarkably, the BCR–ABL1 protein itself triggered the production of the BTK splice variants, a finding consistent with previous studies showing that BCR–ABL1 induces the expression of proteins involved in RNA splicing.