Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy.
Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy.
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DOI：
10.1038/s41375-021-01391-2
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Meyer SC
中科院分区：
文献类型：
--
作者：
Brkic S;Stivala S;Santopolo A;Szybinski J;Jungius S;Passweg JR;Tsakiris D;Dirnhofer S;Hutter G;Leonards K;Lischer HEL;Dettmer MS;Neel BG;Levine RL;Meyer SC
骨髓增生性肿瘤（MPN）显示JAK 2信号传导失调。JAK 2抑制剂提供临床益处，但MAPK通路信号传导的代偿性激活阻碍功效。我们假设JAK 2和ERK 1/2的双重靶向可以增强克隆控制和治疗效果。我们在Jak 2 V617 F MPN小鼠、细胞和患者临床分离株中采用了ERK 1/2的遗传和药理学靶向。Jak 2 V617 F与野生型骨髓（BM）的竞争性移植显示，造血中的ERK 1/2缺陷减轻了MPN特征，并减少了血液和造血祖细胞隔室中的Jak 2 V617 F克隆。ERK 1/2消融与JAK 2抑制相结合抑制MAPK转录程序，使细胞分裂正常化并促进克隆控制，表明双重JAK 2/ERK 1/2靶向作为增强的纠正方法。Ruxolitinib和ERK抑制剂联合药理学JAK 2/ERK 1/2抑制可降低Jak 2 V617 F细胞的增殖，并纠正Jak 2 V617 F 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。在MPLW 515 L驱动的MPN中，BM纤维化显著降低至JAK 2抑制剂单一疗法未观察到的程度。JAK 2 V617 F患者的CD 34+血液和BM的集落形成受到PV、ET和MF亚群中JAK 2/ERK 1/2联合抑制的剂量依赖性抑制。总体而言，我们观察到JAK 2和ERK 1/2的双重靶向能够增强治疗效果，这表明MPN的一种新的治疗方法。
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.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
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影响因子：
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