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Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy
Leukemia ( IF 12.8 ) Pub Date : 2021-09-03 , DOI: 10.1038/s41375-021-01391-2
Sime Brkic 1 , Simona Stivala 1 , Alice Santopolo 1 , Jakub Szybinski 1 , Sarah Jungius 1 , Jakob R Passweg 2 , Dimitrios Tsakiris 2 , Stefan Dirnhofer 3 , Gregor Hutter 1 , Katharina Leonards 2 , Heidi E L Lischer 4, 5 , Matthias S Dettmer 6 , Benjamin G Neel 7 , Ross L Levine 8 , Sara C Meyer 1, 2
Affiliation  

Myeloproliferative neoplasms (MPN) show dysregulated JAK2 signaling. JAK2 inhibitors provide clinical benefits, but compensatory activation of MAPK pathway signaling impedes efficacy. We hypothesized that dual targeting of JAK2 and ERK1/2 could enhance clone control and therapeutic efficacy. We employed genetic and pharmacologic targeting of ERK1/2 in Jak2V617F MPN mice, cells and patient clinical isolates. Competitive transplantations of Jak2V617F vs. wild-type bone marrow (BM) showed that ERK1/2 deficiency in hematopoiesis mitigated MPN features and reduced the Jak2V617F clone in blood and hematopoietic progenitor compartments. ERK1/2 ablation combined with JAK2 inhibition suppressed MAPK transcriptional programs, normalized cytoses and promoted clone control suggesting dual JAK2/ERK1/2 targeting as enhanced corrective approach. Combined pharmacologic JAK2/ERK1/2 inhibition with ruxolitinib and ERK inhibitors reduced proliferation of Jak2V617F cells and corrected erythrocytosis and splenomegaly of Jak2V617F MPN mice. Longer-term treatment was able to induce clone reductions. BM fibrosis was significantly decreased in MPLW515L-driven MPN to an extent not seen with JAK2 inhibitor monotherapy. Colony formation from JAK2V617F patients’ CD34+ blood and BM was dose-dependently inhibited by combined JAK2/ERK1/2 inhibition in PV, ET, and MF subsets. Overall, we observed that dual targeting of JAK2 and ERK1/2 was able to enhance therapeutic efficacy suggesting a novel treatment approach for MPN.



中文翻译:

JAK2 和 ERK 的双重靶向干扰骨髓增生性肿瘤克隆并增强治疗效果

骨髓增生性肿瘤 (MPN) 显示 JAK2 信号失调。JAK2 抑制剂提供临床益处,但 MAPK 通路信号的代偿性激活会阻碍疗效。我们假设 JAK2 和 ERK1/2 的双重靶向可以增强克隆控制和治疗效果。我们在Jak2 V617F MPN 小鼠、细胞和患者临床分离株中采用了 ERK1/2 的遗传和药理学靶向。Jak2 V617F 与野生型骨髓 (BM)的竞争性移植表明,造血中的 ERK1/2 缺陷减轻了 MPN 特征并降低了Jak2血液和造血祖细胞隔室中的 V617F 克隆。ERK1/2 消融结合 JAK2 抑制抑制了 MAPK 转录程序,使细胞增多正常化并促进了克隆控制,表明双重 JAK2/ERK1/2 靶向作为增强的纠正方法。联合药物 JAK2/ERK1/2 抑制与 ruxolitinib 和 ERK 抑制剂可减少Jak2 V617F 细胞的增殖并纠正Jak2 V617F MPN 小鼠的红细胞增多和脾肿大。长期治疗能够诱导克隆减少。MPL W515L 驱动的 MPN中 BM 纤维化显着降低到 JAK2 抑制剂单一疗法未见的程度。JAK2 V617F 患者的 CD34 +集落形成PV、ET 和 MF 亚群中 JAK2/ERK1/2 联合抑制对血液和 BM 的抑制呈剂量依赖性。总的来说,我们观察到 JAK2 和 ERK1/2 的双重靶向能够提高治疗效果,这表明一种新的 MPN 治疗方法。

更新日期:2021-09-04
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