Genetic characterization and drug sensitivity study of newly derived HGBL double/triple-hit lymphoma cell lines

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (HGBL-D/TH) is a group of aggressive lymphomas with poor clinical outcome following standard immunochemotherapy. A panel of cell lines faithfully representing this lymphoma is desirable for further understanding its biology and developing better treatment regimens. We generated one double hit (COH-DHL) and one triple hit cell line (COH-THL1) from two patients. The two cell lines were extensively characterized, along with two reported lines CS-THL1 and DOGKIT. The data were compared with four previously described D/TH lymphoma lines and one BL line, Jijoye. The D/TH lymphoma cell lines showed similar expression profile to BL and DLBCL with closer similarity to BL. Many of the frequent mutations (CREBBP, KMT2D, EP300 and EZH2) were shared with FL and GCB-DLBCL. Genomic copy number abnormalities (gCNAs) showed that these lines had more gains than losses with some of these harboring know oncogenes or tumor suppressor genes. Genes within the gCNA were enriched in pathways regulating apoptosis, cell cycle, and TGFB, TP53, NF-kB, PKA and interferon signaling. Five D/TH lymphoma cell lines and Jijoye, were treated with 10 different drugs targeting Myc and/or BCL2 and other critical cellular pathways. Silvestrol and Dinaciclib generally showed outstanding activities and the newly derived cell lines tended to be most responsive. The BL cell line Jijoye showed a completely different pattern of response. A panel of well characterized D/TH lymphoma lines would be very helpful in preclinical studies of targeted agents.