The absence of SLP65 sand Btk blocks B cell development at the preB cell receptor-positive stage

Mice deficient for the adapter protein SLP65 (BLNK) show a partial block in early B cell development, reduced numbers of mature B cells. in the periph ery, an absence of Bl cells and a reduction of IgM and IgG3 serum immunoglo bulin levels. A strikingly similar phenotype is observed in Bt[c-deficient mice. To investigate the consequences of mutations in both SLP65 and Btk, w e generated SLP65/Btk double-mutant mice by crossing the single-mutant mice . Analysis of the double-mutant mice reveals a much more severe defect in B cell development. B cells in the SLP65/Btk double-mutant mice are arrested at the preB cell stage and, surprisingly, express the preB cell receptor. Normally, preB cell receptor expression in wild-type mice is restricted to a very small fraction of B cells making it difficult to identify these cell s in the bone marrow. Together, the data demonstrate the synergistic role o f SLP65 and Btk in B cell development and describe a situation where large numbers of preB cell receptor-positive cells accumulate in the bone marrow and spleen.