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DUSP6介导对JAK2抑制的抵抗并驱动白血病进展

原文发布日期：2022-12-29

英文摘要：

摘要翻译：

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DUSP6介导对JAK2抑制的抵抗并驱动白血病进展

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

原文发布日期：2022-12-29

英文摘要：

Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across Jak2V617F and MPLW515L MPN mouse models and sAML PDXs without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and highlight the DUSP6–RSK1 axis as a vulnerable, druggable pathway in myeloid malignancies.

摘要翻译：

多核胞性未分化粒细胞瘤(MPNs)表现出向次发急性髓性白血病(sAML)转变的趋势，其转位机制尚不完全明了，这导致治疗选项有限，临床疗效欠佳。我们在研究中对一系列MPN和sAML患者干细胞及祖粒细胞进行了单细胞RNA测序分析，发现该过程中存在DUSP6异常上调表达，可能是疾病转位的潜在驱动力。药理学上的双重特定性磷酸酶抑制剂(Dual-Specificity Phosphatase)针对DUSP6发挥作用时，不仅能够抑制S6蛋白以及JAK-STAT信号通路的激活，并且减少炎症因子的产生。此外，DUSP6干扰还能进一步抑制核糖体S6激酶(RSK1)，我们发现这可能是与患者预后相关的第二种关键分子。过表达异常DUSP6则可诱导JAK2抑制剂耐药并加重患者脱氧核苷酸转移酶激活因子表达，这在患者的脱氧核苷酸转移酶激活因子过表达的异基因瘤(PDX)模型中表现得更为明显。相反地，DUSP6抑制剂对Jak2V617F和MPLW515L小鼠MPN模型以及sAML PDX模型中的疾病进展具备强有力的抑制作用，并且在健康对照中并未引发毒性反应。这些发现加深了我们对DUSP6在驱动疾病转位中的认识，并将DUSP6-RSK1轴线作为治疗白血病中可靶向破坏的关键通路。