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Bruton's Tyrosine Kinase Cooperates with the B Cell Linker Protein SLP-65 as a Tumor Suppressor in Pre-B Cells

Rogier Kersseboom¹, Sabine Middendorp¹, Gemma M. Dingjan¹, Katarina Dahlenborg¹, Michael Reth², Hassan Jumaa² and Rudolf W. Hendriks¹

¹ Department of Immunology, Erasmus MC Rotterdam, P.O. Box 1738, NL-3000 DR Rotterdam, Netherlands
² Institute for Biology III, Albert-Ludwigs University of Freiburg, and Max Planck Institute for Immunobiology, Stuebeweg 51, 79108 Freiburg, Germany

Address correspondence to R.W. Hendriks, Department of Immunology, Erasmus MC Rotterdam, Dr. Molewaterplein 50, P.O. Box 1738, NL-3000 DR Rotterdam, Netherlands. Phone: 31-10-4087181; Fax: 31-10-4089456; E-mail: r.hendriks{at}erasmusmc.nl

Expression of the pre-B cell receptor (pre-BCR) leads to activation of the adaptor molecule SLP-65 and the cytoplasmic kinase Btk. Mice deficient for one of these signaling proteins have an incomplete block in B cell development at the stage of large cycling pre-BCR⁺CD43⁺ pre-B cells. Our recent findings of defective SLP-65 expression in 50% of childhood pre-B acute lymphoblastic leukemias and spontaneous pre-B cell lymphoma development in SLP-65^-/- mice demonstrate that SLP-65 acts as a tumor suppressor. To investigate cooperation between Btk and SLP-65, we characterized the pre-B cell compartment in single and double mutant mice, and found that the two proteins have a synergistic role in the developmental progression of large cycling into small resting pre-B cells. We show that Btk/SLP-65 double mutant mice have a dramatically increased pre-B cell tumor incidence (75% at 16 wk of age), as compared with SLP-65 single deficient mice (<10%). These findings demonstrate that Btk cooperates with SLP-65 as a tumor suppressor in pre-B cells. Furthermore, transgenic low-level expression of a constitutive active form of Btk, the E41K-Y223F mutant, prevented tumor formation in Btk/SLP-65 double mutant mice, indicating that constitutive active Btk can substitute for SLP-65 as a tumor suppressor.

Key Words: Btk • lymphoma • precursor-B cell • SLP-65/BLNK • tumor suppressor

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