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

ABSTRACT: Multiple myeloma (MM) remains a challenging 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 synergizes with various anti-MM compounds, and inhibits MM growth in primary patient samples as well as xenograft mouse models. Collectively, our study uncovers WNK1 as a potential therapeutic target in MM.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wen Liu

PROVIDER: PXD051532 | iProX | Thu Apr 18 00:00:00 BST 2024

REPOSITORIES: iProX

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