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Redundancy in B Cell Developmental Pathways: c-Cbl Inactivation Rescues Early B Cell Development through a B Cell Linker Protein-Independent Pathway¹

Haifeng Song^*, Juan Zhang, Y. Jeffrey Chiang^*, Reuben P. Siraganian and Richard J. Hodes^2,*,

^* Experimental Immunology Branch, National Cancer Institute, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, and National Institute on Aging, National Institutes of Health, Bethesda, MD 20892

Deficiency in the adaptor protein B cell linker protein (BLNK) results in a substantial but incomplete block in B cell development, suggesting that alternative pathways exist for B lineage differentiation. Another adaptor protein, c-Cbl, plays a negative regulatory role in several BCR-signaling pathways. We therefore investigated the role of c-Cbl during B cell development and addressed the possibility that redundancies in pathways for B cell differentiation could be further revealed by eliminating negative effects mediated by c-Cbl. Strikingly, c-Cbl inactivation reversed a number of the critical defects in early B cell differentiation that are seen in BLNK-deficient mice. c-Cbl^–/–BLNK^–/– mice exhibited normalized down-regulation of pre-BCR and CD43, up-regulation of MHC class II, and augmented L chain rearrangement, resulting in a successful transition from pre-B cells to immature B cells. c-Cbl inactivation also reversed the potentially tumor-predisposing hyperproliferative response of BLNK^–/– pre-B cells to IL-7. Pre-BCR cross-linking induced enhanced and prolonged tyrosine phosphorylation in c-Cbl^–/–BLNK^–/– pre-BCR⁺ pre-B cells compared with c-Cbl^+/–BLNK^–/– cells, including elevated phosphorylation of Lyn, Syk, Btk, and phospholipase C-2. Our studies suggest that some, but not all, pre-BCR-triggered developmental events can be mediated by BLNK-independent pathways that are negatively regulated by c-Cbl, and further suggest that different events during early B cell development require different strength or duration of pre-BCR signaling.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research and the National Institute of Dental Research, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Richard J. Hodes, National Institute on Aging, National Institutes of Health, Building 10, Room 4B10, 9000 Rockville Pike, Bethesda, MD 20892. E-mail address: hodesr{at}31.nia.nih.gov

³ Abbreviations used in this paper: PTK, protein tyrosine kinase; BLNK, B cell linker protein; PLC, phospholipase C; LAT, linker for activation of T cells; SH, Src homology; BM, bone marrow; MFI, mean fluorescence intensity; MZ, marginal zone; FO, follicular; pre-BCR, precursor BCR; c-Cbl, Casitas B-lineage lymphoma proto-oncogene c; SLC, surrogate L chain.