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Extensive research has been performed regarding the integration sites of murine leukemia retrovirus (MLV) for the identification of proto-oncogenes. To date, the overlap of mutations within specific oligonucleotides across different tumor genomes has been regarded as a rare event; however, a recent study of MLV integration into the oncogene Zfp521 suggested the existence of a hotspot oligonucleotide for MLV integration. In the current review, we discuss the hotspots of MLV integration into several genes: c-Myc, Stat5a and N-myc, as well as ZFP521, as examined in tumor genomes. From this, MLV integration convergence within specific oligonucleotides is not necessarily a rare event. This short review aims to promote re-consideration of MLV integration within the tumor genome, which involves both well-known and potentially newly identified and novel mechanisms and specifications.

ZFP521was previously identified as a putative gene involved in induction of B-cell lymphomagenesis. However, the contribution of ZFP521to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521in B-cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTKand BANK1were positively regulated by the ZFP521gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-mycand c-junwere upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-mycand c-junand of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTKand BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521in humans, was upregulated. In conclusion, our data showed that the ZFP521gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway.