IRF2 is an Essential Transcription Factor with Pathogenic and Prognostic Impact in Multiple Myeloma.

Multiple Myeloma (MM), the second most prevalent hematologic malignancy, remains incurable, highlighting the need to identify molecular drivers of disease progression and new therapies. Using a CRISPR-Cas9 library screening approach in MM cells, we identified 22 essential transcription factors (TFs), including members of the interferon regulatory factor (IRF) family. Remarkably, in addition to the well-known IRF4, IRF2 emerged as a critical TF in MM. Cut&Run experiments demonstrated that IRF2 binds extensively to chromatin, both independently and in cooperation with IRF1 and IRF4. While IRF2-unique regions were predominantly associated with active promoters, regions bound by IRF2/1/4 were biased towards introns. Functionally, IRF2 contributes to MM cell survival by suppressing necroptosis and promoting cell migration. Notably, IRF2-dependent transcriptional dysregulation was evident in precursor conditions such as MGUS and SMM, suggesting a role in early disease evolution. In addition to its role as early factor, IRF2 levels also seem to influence disease progression, as MMs with higher expression showed worse progression-free survival (PFS) and overall survival (OS) in both univariate and multivariate analyses, even after adjusting for common MM genetic risk factors. In conclusion, IRF2 constitutes an underappreciated essential TF involved in the pathogenesis and clinical behavior of MM. Its inhibition leads to dysregulation of key signaling pathways in MM pathogenesis, highlighting its potential as a therapeutic target.