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.

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。