Bruton's tyrosine kinase cooperates with the B cell linker protein SLP-65 as a tumor suppressor in Pre-B cells
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.
|Keywords||Animals, B-Lymphocytes/*immunology, Carrier Proteins/*physiology, Cells, Cultured, Flow Cytometry, Hematopoietic Stem Cells/*immunology, Leukemia, Pre-B-Cell/*prevention & control, Lymphoma, B-Cell/*prevention & control, Mice, Mice, Inbred C57BL, Phosphoproteins/*physiology, Protein-Tyrosine Kinase/*physiology, Research Support, Non-U.S. Gov't, Tumor Suppressor Proteins/*physiology|
Kersseboom, R., Middendorp, S., Dingjan, G.M., Dahlenborg, K., Reth, M., Jumaa, H., & Hendriks, R.W.. (2003). Bruton's tyrosine kinase cooperates with the B cell linker protein SLP-65 as a tumor suppressor in Pre-B cells. The Journal of Experimental Medicine. Retrieved from http://hdl.handle.net/1765/8407