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Clonal selection and double hit events involving tumor suppressor genes underlie relapse from chemotherapy: myeloma as a model

Niels Weinhold, Cody Ashby, Leo Rasche, Shweta S. Chavan, Caleb Stein, Owen W. Stephens, Ruslana Tytarenko, Michael A. Bauer, Tobias Meissner, Shayu Deshpande, Purvi H. Patel, Timea Buzder, Gabor Molnar, Erich A. Peterson, Frits van Rhee, Maurizio Zangari, Sharmilan Thanendrarajan, Carolina Schinke, Erming Tian, Joshua Epstein, Bart Barlogie, Faith E. Davies, Christoph J. Heuck, Brian A. Walker and Gareth J. Morgan

Key points

  • Hits in driver genes and bi-allelic events affecting tumor suppressors increase apoptosis resistance and proliferation rate driving relapse.

  • Excessive bi-allelic inactivation of tumor suppressors in high risk cases highlight the need for TP53 independent therapeutic approaches.

Abstract

To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high resolution copy number arrays and whole exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of bi-allelic inactivation events affecting tumor suppressor genes, especially TP53. The end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian type clonal evolution. The number of copy number aberration changes and bi-allelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma propagating cells to survive multi-agent chemotherapy and to result in relapse.

  • Submitted June 23, 2016.
  • Accepted August 2, 2016.