Identification of WNK1 as a therapeutic target to suppress IgH/MYC expression in multiple myeloma

Multiple myeloma (MM) remains an incurable hematological malignancy demanding innovative therapeutic strategies. Targeting MYC, the notorious yet traditionally undruggable oncogene, presents an appealing avenue. Here, using a genome-scale CRISPR-Cas9 screen, we identify the WNK lysine-deficient protein kinase 1 (WNK1) as a regulator of MYC expression in MM cells. Genetic and pharmacological inhibition of WNK1 reduces MYC expression and, further, disrupts the MYC-dependent transcriptional program. Mechanistically, WNK1 inhibition attenuates the activity of the immunoglobulin heavy chain (IgH) enhancer, thus reducing MYC transcription when this locus is translocated near the MYC locus. WNK1 inhibition profoundly impacts MM cell behaviors, leading to growth inhibition, cell-cycle arrest, senescence, and apoptosis. Importantly, the WNK inhibitor WNK463 inhibits MM growth in primary patient samples as well as xenograft mouse models and exhibits synergistic effects with various anti-MM compounds. Collectively, our study uncovers WNK1 as a potential therapeutic target in MM. [Display omitted] •CRISPR screen identifies WNK1 as a regulator of MYC expression in MM•WNK1 inhibition attenuates the IgH enhancer activity to suppress IgH/MYC expression•WNK1 inhibition suppresses MM growth in vitro and in vivo•WNK463 synergizes with anti-MM drugs Ye et al. report the identification and characterization of WNK1 as a regulator of MYC expression in multiple myeloma by modulating the IgH enhancer. Genetic and pharmacological inhibition of WNK1 reduces the expression of MYC and other IgH translocation partners, suppressing multiple myeloma cell growth in vitro and in vivo.