Balancing proliferation with Igκ recombination during B-Iymphopoiesis

The essential events of B-cell development are the stochastic and sequential rearrangement of immunoglobulin heavy (Ig mu) and then light chain (Ig kappa followed by Ig lambda) loci. The counterpoint to recombination is proliferation, which both maintains populations of pro-B cells undergoing Ig mu, recombination and expands the pool of pre-B cells expressing the Ig mu, protein available for subsequent Igk recombination. Proliferation and recombination must be segregated into distinct and mutually exclusive developmental stages. Failure to do so risks aberrant gene translocation and leukemic transformation. Recent studies have demonstrated that proliferation and recombination are each affected by different and antagonistic receptors. The 11,7 receptor drives proliferation while the pre-B-cell antigen receptor, which contains Ig mu, and surrogate light chain, enhances Igk accessibility and recombination. Remarkably, the principal downstream proliferative effectors of the 11,7R, STAT5 and cyclin D3, directly repress Igk accessibility through very divergent yet complementary mechanisms. Conversely, the pre-B-cell receptor represses cyclin D3 leading to cell cycle exit and enhanced Igk accessibility. These studies reveal how cell fate decisions can be directed and reinforced at each developmental transition by single receptors. Furthermore, they identify novel mechanisms of Igk repression that have implications for gene regulation in general.