RNA-seq analysis of human multiple myeloma cell lines treated with pyridostatin and panobinostat

Multiple Myeloma is the second most frequent blood cancer, characterized by clonal proliferation of terminally differentiated plasma cells (PCs) in the bone marrow (BM)1. Despite considerable progress in the treatment of MM, particularly with the emergence of immune-based therapies, it remains unclear how to overcome drug resistance, especially in high-risk patients with TP53 abnormalities including del17p and/or TP53 mutations2–4. Deregulated oncogene expression can alter replication timing and transcriptional programs, resulting in increased replication stress (RS), generally referred to as oncogene-induced RS5. Accordingly, MM cells (MMCs) but not normal PCs exhibit constitutive phosphorylation of the RS marker H2A.X (termed H2A.X)6. Oncogene overexpression also results in hyperactivation of the transcriptional machinery required to sustain increased proliferation and cell growth7,8. Hypertranscription thus exacerbates RS by impeding replication fork progression, often resulting in transcription-replication conflicts (TRCs). MMCs must cope with both oncogene-induced RS and a high level of transcription linked to immunoglobulin (Ig) synthesis, thus constituting a positive loop that sustains genomic instability. In line with this, increased transcription in MM has been associated with increased mutation rate9. This genomic instability is therefore an Achilles heel for MMCs, which are expected to be more dependent on the DNA damage response (DDR) for survival than normal PCs, offering exploitable targets for the development of new therapeutic strategies. To understand how pyridostatin (PDS) increases the potency of lenalidomide (Lena), we performed a transcriptomic analysis using three different multiple myeloma cell lines. In this experiment, we evaluate the response after 48h of treatment with the combination of compound PDS at 2.5µM, and of compound lenalidomide (XG7, JJN3: 25µM), XG20:50µM) in three multiple myeloma cell lines (XG20, XG7, JJN3)