Target the Dusp1 in Jak2 dependent myeloproliferative neoplasm (MPN) for curative treatment

尽管酪氨酸激酶抑制剂(TKI)在临床上作为一种抗癌药物的治疗效果令人印象深刻 治疗，它是不能治愈的。即使是最有效的激酶抑制剂也对小剂量的 对治疗不敏感的癌细胞群体；表现为微小的残留病 (MRD)。同样，用JAK2抑制剂治疗的骨髓增生性疾病显示出对 TKI治疗。失败会导致治疗后复发，导致持久性细胞消失。治疗性的 对TKI的反应是由癌基因成瘾介导的；然而，控制TKI的分子机制 在致癌基因成瘾的背景下，TKI诱导的细胞死亡尚不清楚。我们发现 MAPK磷酸酶，DUSP1，是癌基因成瘾的关键介质，由突变驱动的MPD JAK2、MPL和CSF3R。DUSP1在MPDS中的过表达消除癌基因成瘾和消融 TKI回应。DUSP1的遗传和药理抑制对JAK2-V761F的合成致死作用 和CSF3R-T618I驱动的MPD。这项拟议的研究将解决小鼠模型的敏感性 MPD白血病启动细胞和原发患者样本对单独干扰DUSP1活性和 在TKI治疗的背景下。此外，我们还建议开发特异和有效的DUSP1抑制剂 利用结构功能研究进行临床应用。我们的结果应该会加速 一种治疗多发性硬化症的疗法。

Despite the impressive response to tyrosine kinase inhibitor (TKI) therapy in the clinic as an anti-cancer treatment, it is not curative. Even the most potent kinase inhibitors are ineffective against a small population of cancer cells, which are insensitive to treatment; manifesting as minimal residual disease (MRD). Likewise, myeloproliferative disorders treated with Jak2 inhibitors show intrinsic resistance to TKI treatment . Failure eradicate the persistent cells them leads to post-therapy relapse. Therapeutic response to TKI is mediated by oncogene-addiction; however, the molecular mechanisms governing TKI-induced cell death in the context of oncogene-addiction is not clearly understood. We find that MAPK phosphatase, Dusp1, is a critical mediator of oncogene-addiction in MPD driven by mutations in JAK2, MPL and CSF3R. Overexpression of Dusp1 in MPDs abrogates oncogene addiction and ablates TKI response. Both genetic and pharmacological inhibition of Dusp1 is synthetic lethal to Jak2-V761F and CSF3R-T618I driven MPDs. The proposed research will address the sensitivity of murine-model of MPD leukemia initiating cells and primary patient specimens to disrupting Dusp1 activity alone and in the context of TKI therapy. In addition, we propose to develop specific and potent Dusp1 inhibitor using structure function studies for clinical application. Our results should accelerate development of a curative therapy for MPDs.