Burkitt’s lymphoma is characterised by the t(8;14)(q24;32) translocation, which juxtaposes MYC to IGH enhancer elements (Dalla-Favera, et al. 1982). The Eμ-Myc mouse model employs a transgene mimicking the t(8;14) translocation; these mice develop Burkitt-like B-cell leukaemia/lymphoma with 100% penetrance (Adams, et al. 1985). The current paradigm is that secondary mutations must occur along with constitutive MYC overexpression to act as the initiating event capable of shifting Eμ-Myc tumours from a pre-malignant stage to clonal lymphoid neoplasia. It is known that there is disruption in the archetypal tumour suppressor pathway involving the cdnk2a and trp53 lociin at least 50% of spontaneous Eμ-Myc lymphoma (Eischen, et al. 1999). However, the lesions required to cooperate with MYC in the remaining 50% are unknown. The identification of genes that cooperate with MYC could therefore yield not only new biological insight into oncogenic pathways involved in B-cell lymphomagenesis but also improve therapy for patients in the future.
In this study, 26 spontaneous Eμ-Myc lymphomas were exome re-sequenced to determine novel somatic ‘driver’ mutations. From this screen we found that Bcl6 co-repressor (Bcor) harboured loss-of-function mutations at high frequency (6/26). By transducing Eμ-Myc foetal liver cells with Bcor-targeting short hairpin RNA (shRNA.Bcor) we found that loss of BCOR expression with constitutive MYC overexpression rapidly accelerates lymphomagenesis.
BCOR loss-of-function mutations have recently been identified in cytogenetically normal acute myeloid leukaemia (CN-AML), chronic lymphocytic leukaemia (CLL) and retinoblastoma but have not yet been validated as a genuine tumour suppressor gene (Grossmann, et al. 2011; Quesada, et al. 2011; Zhang, et al. 2012). This is the first study to date to show that Bcor loss-of-function mutations accelerate lymphomagenesis in a model of Burkitt-like leukaemia/B-ALL. Given that BCOR mutations are prevalent in the clinic, we hypothesise that Bcor is an important, clinically relevant putative tumour suppressor gene, whereby loss-of-function mutations cooperate with Myc to drive lymphomagenesis.