1. Academic Validation
  2. Identification of WNK1 as a therapeutic target to suppress IgH/MYC expression in multiple myeloma

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

  • Cell Rep. 2024 May 28;43(5):114211. doi: 10.1016/j.celrep.2024.114211.
Tianyi Ye 1 Alok K Mishra 2 Shahid Banday 2 Rui Li 2 Kai Hu 2 Madison M Coleman 2 Yi Shan 2 Shreya Roy Chowdhury 2 Lin Zhou 2 Magnolia L Pak 2 Tessa M Simone 2 Sunil K Malonia 2 Lihua Julie Zhu 2 Michelle A Kelliher 2 Michael R Green 2
Affiliations

Affiliations

  • 1 Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: tianyi.ye@umassmed.edu.
  • 2 Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Abstract

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.

Keywords

CP: Cancer; CRISPR screen; IgH translocation; MYC; WNK1; multiple myeloma.

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