What ever Pax5 soweth... The salient features of B-cell development are immunoglobulin gene rearrangements, class switching recombinations (CSRs) and somatic hypermutations (SHMs). Collectively, these processes account for the diversity of antibodies, as well as for affinity maturation of antibodies in germinal centers. However, the propensity of Bcells to undergo genetic alterations has unintended consequences–that is, a high frequency of oncogenic events. These events clearly inform lymphomagenesis: translocated and otherwise altered genes inevitably turn out to be oncogenes playing an important role in tumor initiation. For example, Burkitt’s and some diffuse large B-cell lymphomas (DLBCLs) carry the t (8; 14) translocation that places the MYC protooncogene under control of the Igh enhancer (for a recent review see [1]). Another transcription factor affected by translocations is Pax5. Pax5 belongs to a family of nine nuclear proteins that are thought to control the tissue-specific transcription necessary for many types of cell differentiation. Pax5 is the only family member found within the hematopoietic system, and its expression is restricted to certain stages during B-cell differentiation [2]. It is largely absent from multipotent progenitors and common lymphoid progenitors [3], but its expression is initiated in pre-pro-B cells and then maintained throughout subsequent stages of B-cell development [4] before it is downregulated in plasma cells [5]. However, Pax5 is unique among other lineage-specific transcription factors in that it is both a driving force behind and one of the primary beneficiaries (or perhaps sufferers) of genomic alterations.

Indeed, one of its important targets is the Rag-2 gene encoding recombination-activating protein 2 [6, 7]. During VH–DJH recombination, the RAG1/RAG2 complex introduces doublestranded DNA breaks that ultimately rejoin to generate functional heavy chain cassettes. The same process is thought to underlie illegitimate recombination, during which Ig heavy chain enhancers will be juxtaposed to one of the B-cell oncogenes such as Myc, Bcl2, Bcl1 and so on. In addition to activating the Rag2 gene, Pax5 occupies VH genes in early human and mouse B-lineage cells, induces Igh locus contraction [8], and physically interacts with the RAG1/RAG2 complex, thus promoting recombination events [9]. Importantly, the VH–DJH recombination cannot happen in the presence of lysine-9-methylated histone H3, and the removal of this inhibitory signal in B cells is an important function of Pax5 [10]. Consequently, only a minor fraction of lymphocytes in Pax5-null mice have completed VH–DJH rearrangement and most are arrested at the earlier, pro-B stage [11]. Recent data indicate that Pax5 might also play a role in light chain locus contraction [12]. Additionally, Pax5 is known to be required for the expression of Igα [13], a sIgM-associated signaling molecule, which is the key component of the B-cell receptor (BCR; reviewed in [14]). CSR, which might also contribute to oncogenic translocations, and SHM are less wellunderstood processes. However, recent work has implicated activation-induced cytidine deaminase (AID) in both phenomena. Interestingly, Pax5 is known to activate AID [15, 16] and can therefore contribute to CSR and SHM also. Overall, while Pax5 might be a guardian of B-cell identity [2], it is a curiously permissive one with respect to genome integrity.