Primary mediastinal large B-cell lymphoma (PMBL) cells depend on the constitutive activity of NFκB and STAT transcription factors, which drive expression of multiple molecules essential for their survival. We have previously showed that in a molecularly-related B-cell malignancy, classical Hodgkin lymphoma (cHL), tumor Reed-Sternberg (RS) cells overexpress oncogenic PIM1/2/3 kinases (PIMs) in a NFκB- and STAT-dependent manner, and that PIMs enhance survival and expression of immunomodulatory molecules. Given the multiple overlapping characteristics of RS and PMBL cells, we hypothesized that PIM kinases may be overexpressed in PMBL and be involved in PMBL pathogenesis. Herein, we assessed the expression of PIM kinases in PMBL diagnostic biopsies and determined their role in survival and immune escape of the tumor cells. PIMs were abundantly expressed in primary tumors and PMBL cell lines. Inhibition of PIM kinases was toxic to PMBL cells, attenuated protein translation and downregulated NFκB-/STAT-dependent transcription of pro-survival factors BCL2A1, BCL2L1 and FCER2. Furthermore, PIM inhibition decreased expression of molecules engaged in shaping the immunosuppressive microenvironment, including PD-L1/2 and CCL17. Taken together, our data demonstrate that PIMs support PMBL cell survival and immune escape, and identify PIMs as promising therapeutic targets in PMBL.
Copyright © 2020. Published by Elsevier Inc.