Poster Presentation 26th Lorne Cancer Conference 2014

The oncogenic functionality of JAK2 and PD-L1 to Eµ-Myc lymphoma (#157)

Gareth Gregory 1 2 , Marcus Lefebure 1 2 , Stephen Mattarollo 3 4 , Benjamin P Martin 1 , Tony Papenfuss 2 4 5 , Meaghan Wall 6 , Richard Tothill 1 7 8 , Jake Shortt 1 2 , Ricky W Johnstone 1 2 7
  1. Gene Regulation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  3. Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia
  4. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  5. Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  6. Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Melbourne, Victoria, Australia
  7. Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  8. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

The Eµ-Myc transgenic mouse provides a tractable tool for dissecting mechanisms of B-lineage lymphomagenesis and efficacy of novel therapeutics. We performed genomic profiling of Eµ-Myc lymphomas to identify genetic lesions co-operating with Myc in de novo lymphomagenesis. Whole genome sequencing and FISH mapped the original insertion of the Eµ-Myc transgene into chromosome 19 with associated germline amplification of an adjacent chromosomal segment including the loci for Jak2 and Cd274 (encoding PD-L1). Additional copy number gains of this amplicon occurred in half of sequenced tumours indicating potential co-operativity between the Myc transgene and adjacent amplified elements such as Jak2. Importantly, amplification of the syntenic human chromosome 9p24.1 is described in primary mediastinal B-cell lymphoma and Hodgkin lymphoma putatively conferring increased signalling through the canonical JAK/STAT pathway and increased PD-L1 transcript abundance.1  We therefore hypothesised this amplicon to be functionally oncogenic to Eµ-Myc lymphoma.

Eµ-Myc lymphomas did not show biochemical evidence of activated canonical JAK/STAT signalling despite Jak2 copy-number gains. Moreover, Eµ-Myc lymphomas were resistant to pharmacological JAK2 inhibition in vitro and in vivo.  Over-expression of constitutively active (V617F) JAK2 in Eµ-Myc haematopoietic progenitor cells failed to accelerate lymphomagenesis as compared to nRAS Q61K-controls. Consistent with the JAK2 data, surface expression of PD-L1 by FACS analysis did not correlate with amplicon dose and, in contrast to a PD-L1HI MC38 colon-cancer cell line, JAK2 inhibition did not down-regulate PD-L1 expression on Eµ-Myc cells. However, in vivo treatment with PD-L1 blocking antibody improved survival in lymphoma-bearing mice.

These results indicate that Jak2 does not co-operate with Myc in lymphomagenesis and that pharmacological inhibition of JAK2 is not a favourable therapeutic strategy in aggressive Myc-driven lymphoma. Interestingly however, PD-L1 expression levels were not predictive of in vivo responses suggesting that the efficacy of PD-L1 blockade is not restricted to tumours with genetic amplification.  The functional significance of 9p amplifications in human lymphoma requires further investigation. 

  1. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–3277