Multi-omic Analysis of B-Cell Lymphoma Reveals Novel Mechanisms of Chemotherapeutic Drug Resistance

The genetic origins of chemotherapy resistance are well established, however the role of the epigenome and post-transcriptional regulation in drug resistance is less well understood. To investigate mechanisms of drug resistance we performed a systematic genetic, epigenetic, transcriptomic and proteomic analysis of a mafosfamide sensitive and resistant murine lymphoma cell line, along with a series of resistant lines derived by drug dose escalation. Our data suggest that acquired resistance could not be explained by genetic alterations. By integrating our transcriptional profiles with transcription factor binding data we hypothesize that the resistance was associated with changes in the activity of the polycomb repressive complex (Prc2) as well as the transcription factor E2a. We verified that the resistant cells had distinct H3K27me3 and DNA methylation profiles, compared to the parental lines, and differentially expressed genes were enriched for targets of E2a. In addition, the resistant lines appear to de-differentiate to a less mature state along the B cell maturation axis. Overall, we propose that resistant lines are transformed by an E2a and Pcr2 driven cellular program that leads to a less mature B cell state in which the apoptotic cascade induced by mafosfamide treatment is attenuated. Furthermore, combined transcriptomic and proteomic data analysis elucidated mechanisms of resistance involving the ubiquitination activating enzyme Uba1 which were not revealed by analysis of either transcriptomic or proteomic data alone