Poster Presentation 25th Lorne Cancer Conference 2013

Bcor loss-of-function mutations cooperate with Myc to drive lymphomagenesis in Eμ-Myc lymphoma. (#244)

Marcus Lefebure 1 , Geoff Matthews 1 , Ben Martin 1 , Jake Shortt 1 , Eva Vidacs 1 , Edwin Hawkins 1 , Elizabeth Kruse 1 , Maria Doyle 1 , Timothy Semple 1 , Timothy Holloway 1 , Richard Tothill 1 , Ricky W Johnstone 1
  1. Peter MacCallum Cancer Centre, East Melbourne, Australia

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.

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