Bruton's tyrosine kinase cooperates with the B cell linker protein SLP-65 as a tumor suppressor in Pre-B cells.

Abstract

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 approximately 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 ( approximately 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.

• Authors: Rogier Kersseboom, Sabine Middendorp, Gemma M Dingjan, Katarina Dahlenborg, Michael Reth, Hassan Jumaa, Rudolf W Hendriks
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 198 Issue 1 Pg. 91-8 (Jul 07 2003) ISSN: 0022-1007 [Print] United States
• PMID: 12835482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• B cell linker protein
• Carrier Proteins
• Phosphoproteins
• Tumor Suppressor Proteins
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• Btk protein, mouse

Topics

• Adaptor Proteins, Signal Transducing
• Agammaglobulinaemia Tyrosine Kinase
• Animals
• B-Lymphocytes (immunology)
• Carrier Proteins (physiology)
• Cells, Cultured
• Flow Cytometry
• Hematopoietic Stem Cells (immunology)
• Lymphoma, B-Cell (prevention & control)
• Mice
• Mice, Inbred C57BL
• Phosphoproteins (physiology)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (prevention & control)
• Protein-Tyrosine Kinases (physiology)
• Tumor Suppressor Proteins (physiology)