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.
摘要：
多发性骨髓瘤（MM）仍然是一种无法治愈的血液恶性肿瘤，需要创新的治疗策略。瞄准MYC,臭名昭著但传统上不可下药的致癌基因，呈现出一条吸引人的大道。这里,使用基因组尺度的CRISPR-Cas9筛选，我们确定WNK赖氨酸缺陷蛋白激酶1（WNK1）是MM细胞中MYC表达的调节剂。WNK1的遗传和药理学抑制降低了MYC表达，进一步,破坏MYC依赖的转录程序。机械上,WNK1抑制减弱免疫球蛋白重链（IgH）增强子的活性，因此，当该基因座易位在MYC基因座附近时，会降低MYC转录。WNK1抑制深刻影响MM细胞行为，导致生长抑制，细胞周期停滞,衰老，和凋亡。重要的是,WNK抑制剂WNK463抑制原发性患者样品以及异种移植小鼠模型中的MM生长,并表现出与各种抗MM化合物的协同作用。总的来说，我们的研究发现WNK1是MM的潜在治疗靶点.
