RIPK1 is aberrantly expressed in multiple B-cell cancers and implicated in the underlying pathogenesis

Abstract

Abstract According to the latest epidemiology of the US, B-cell cancers account for > 3% of all new cancer cases and > 80% of non-Hodgkin lymphomas. However, the disease-modifying small molecular drug suitable for most B-cell cancers is still lacking. RIPK1 (receptor-interacting serine/threonine-protein kinase 1) has been observed to be dysregulated and implicated in the pathogenesis of multiple solid cancers, of which, however, the roles in blood cancers are quite unclear. In our study, to identify multi-function targets for B-cell cancer treatment, we reanalyzed a public transcriptomic dataset from the database of Gene Expression Omnibus, which includes CD19+ B-cell populations from 6 normal donors and patients of 5 CLL, 10 FL, and 8 DLBCL. After overlapping three groups (CLL vs. normal, FL vs. normal, and DLBCL vs. normal) of differentially expressed genes (DEGs), we obtained 69 common DEGs, of which 3 were validated by real-time quantitative PCR, including RIPK3, IGSF3, TGFBI. Interestingly, we found that the loss function of RIPK1 significantly increases the proliferation and viability of GM12878 cells (a normal human B lymphocyte cell line). Consistently, overexpression of RIPK1 in TMD8 and U2932 cells effectively inhibited cell proliferation and growth. More importantly, modifying RIPK1 kinase activity by a small molecule (such as necrostain-1, HOIPIN-1, etc.) alters the cell growth status of B-cell lymphoma, showing that RIPK1 exhibits anti-tumor activity in the context of B-cell lymphoma. Taken together, we consider that RIPK1 may be a potential target in the clinical application of B-cell lymphoma (including CLL, DLBCL, and FL) treatment.

Keywords

• B-cell cancers
• RIPK1
• Necrostain-1
• HOIPIN-1