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. Cleavage under targets and release using nuclease (CUT&RUN) experiments demonstrated that IRF2 binds extensively to chromatin, both independently and in cooperation with IRF1 and IRF4. Although IRF2-unique regions were predominantly associated with active promoters, regions bound by IRF2/1/4 were biased toward 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 monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), suggesting a role in early disease evolution. In addition to its role as an early factor, IRF2 levels also seem to influence disease progression, as MMs with higher expression demonstrated 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.