We have used massively-parallel sequencing to provide a comprehensive analysis of the step-wise progression of cancer in the highly tractable Eμ-Myc mouse model. The Eμ-Myc mouse has been engineered to harbour a t(8;14) translocation juxtaposing the IgH enhancer to the proto-oncogene Myc. Eμ-Myc malignant progression ostensibly occurs as a result of secondary somatic mutations that co-operate with Myc. Despite common perception that the majority of tumours can be explained by disruption of the archetypal Cdkn2a and Trp53 tumour suppressor axis, more than half of spontaneous Eμ-Myc tumours harbor secondary mutations that remain 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.
We applied exome-sequencing to a cohort of 18 spontaneous murine Eμ-Myc lymphomas to determine novel somatic driver mutations. In addition to exome-sequencing, we harvested blood samples at 2-week intervals throughout the premalignant to malignant phases to allow a temporal analysis of mutations that were detected at end-stage. The screen identified mutations in genes previously described in Eμ-Myc lymphoma such as Trp53, Cdkn2a, Kras and Nras. In addition to these mutations, we identified novel protein-truncating mutations in Bcl6 co-repressor (Bcor), which has not previously been described in Eμ-Myc lymphoma. Bcor truncating mutations were present at a high frequency, occurring in 3 out of 18 samples. RNAi mediated knockdown of Bcor in Eμ-Myc fetal liver hematopoietic stem cells reconstituted into lethally irradiated congenic recipient mice accelerated lymphomagenesis, validating Bcor as a tumour suppressor gene in this model.
BCOR loss-of-function mutations have recently been identified in human cancers suggesting that BCOR acts as a tumour-suppressor in a wide range of malignancies. Given that Bcor mutations frequently occur in the Eμ-Myc lymphoma, we hypothesise that Bcor is critically important for B-cell development and that its disruption can induce malignancy in co-operation with other potent oncogenes such as Myc.