CXXC1-dependent IRF4 activity promotes myeloma cell fitness and sustains lenalidomide resistance

Regulation of oncogenic transcriptional programs in multiple myeloma requires the interplay of histone modifications, their writers and readers with lineage-affiliated transcription factors. The transcription factors IKZF1/3, IRF4 and MYC form an aberrant, myeloma-specific regulatory loop that drives myelomagenesis and resistance to immunomodulatory drugs (IMiDs) such as lenalidomide. Chromatin-based mechanisms that regulate these processes remain incompletely understood. Here we investigate the role of CXXC1, a core component of the H3K4 methyltransferase complex COMPASS, in the activity of the IKZF1/3-IRF4-MYC regulatory loop. We find that clinically, high CXXC1 expression is associated with high-risk proliferative, adverse prognosis disease. Consistent with this, CXXC1 is a myeloma dependency and it regulates cellular fitness programs including cell cycle, MYC targets and DNA damage response. High CXXC1 expression in primary myeloma cells is associated with higher chromatin accessibility, while acute depletion of degron-tagged CXXC1 further validates its role in regulating myeloma cell fitness programs and high-risk transcriptional signatures. CXXC1 interacts with and extensively co-binds to chromatin with IRF4 and IKZF3. Notably, in both lenalidomide-sensitive and -resistant myeloma cells, CXXC1 depletion results in loss of IRF4 and IKZF3 chromatin binding and in parallel it 'breaks' the IRF4 transcriptional self-regulatory loop. Thus, CXXC1 and COMPASS emerge as novel therapeutic targets in IMiD-sensitive and -resistant myeloma by regulating the activity of IRF4 and essential myeloma cell fitness programs.