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¹ Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
² Institute for Neurophysiology, University of Cologne, 50931 Cologne, Germany
³ Department of Hematology, University of Frankfurt, 60596 Frankfurt/Main, Germany
⁴ Max-Planck-Institute for Immunobiology, 79108 Freiburg, Germany
⁵ Department of Medicine, University of Chicago, Chicago, IL 60637

CORRESPONDENCE Markus Müschen: markus.mueschen{at}uni-duesseldorf.de

Pre–B cells undergo apoptosis unless they are rescued by pre–B cell receptor–dependent survival signals. We previously showed that the BCR-ABL1 kinase that is expressed in pre–B lymphoblastic leukemia bypasses selection for pre–B cell receptor–dependent survival signals. Investigating possible interference of BCR-ABL1 with pre–B cell receptor signaling, we found that neither SYK nor SLP65 can be phosphorylated in response to pre–B cell receptor engagement. Instead, Bruton's tyrosine kinase (BTK) is constitutively phosphorylated by BCR-ABL1. Activated BTK is essential for survival signals that otherwise would arise from the pre–B cell receptor, including activation of PLC1, autonomous Ca²⁺ signaling, STAT5-phosphorylation, and up-regulation of BCLX_L. Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1⁺ leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself. However, BCR-ABL1 cannot directly bind to full-length BTK. Instead, BCR-ABL1 induces the expression of a truncated splice variant of BTK that acts as a linker between the two kinases. As opposed to full-length BTK, truncated BTK lacks kinase activity yet can bind to BCR-ABL1 through its SRC-homology domain 3. Acting as a linker, truncated BTK enables BCR-ABL1–dependent activation of full-length BTK, which initiates downstream survival signals and mimics a constitutively active pre–B cell receptor.

Abbreviations used: BTK, Bruton's tyrosine kinase; PLC, phospholipase C ; siRNA, small interfering RNA; SAGE, serial analysis of gene expression; SH3, SRC-homology domain 3; SYK, spleen tyrosine kinase; WCL, whole cell lysate.

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