Oncogene-induced senescence: a potential breakpoint mechanism against malignant transformation in plasma cell disorders

Abstract

Oncogene-induced senescence (OIS) is a cellular tumor-suppressive mechanism present in several premalignant conditions. Here, we analyze the possible impact of OIS on malignant transformation in plasma cell disorders. Tumor samples from 125 patients with different disease stages were analyzed immunohistochemically for expression of senescence markers. Protein expression of cyclin-dependent kinase inhibitor p21^Cip1/Waf1 was significantly higher in smoldering multiple myeloma (SMM) compared to monoclonal gammopathy of undetermined significance (MGUS) (p = .02) or symptomatic multiple myeloma (MM) (p = .005). SMM plasma cells expressing p21^Cip1/Waf1 were negative for Ki67, consistent with senescence. While p27^Kip1 was highly expressed in healthy controls, MGUS and SMM, expression decreased significantly in MM (p = .02). SMM plasma cells displayed a mutually exclusive expression of p21^Cip1/Waf1/p27^Kip1 suggesting compensatory mechanisms of senescence. In conclusion, we found markers of cellular senescence differentially expressed in SMM compared to MGUS and MM supporting the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders.

Keywords:

• Hematological malignancy
• multiple myeloma
• MGUS
• senescence
• tumor suppression

Acknowledgements

We thank all patients and their families for participating in this study and we thank Tina Uhrig and Kathrin Jochmann for excellent technical assistance. The authors thank the Tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) for providing the tissue samples in accordance with the regulations of the tissue bank.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1443450.