The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2V617F cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2V617F cells. Accordingly, proliferation and clonogenic potential of JAK2V617F-driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice’s overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2V617F MPN cells and improve MPN patient care.
Janus激酶2（JAK2）驱动的骨髓增殖性肿瘤（MPNs）是一种慢性恶性肿瘤，常伴随高风险并发症，且对鲁索替尼等JAK抑制剂的疗效不佳。为开发新的联合疗法以提高治疗效果，需深入理解鲁索替尼诱导的细胞变化。本研究显示，鲁索替尼通过激活蛋白磷酸酶2A（PP2A）在JAK2V617F细胞系及MPN患者原代细胞中诱发自噬。联合使用自噬或PP2A活性抑制剂与鲁索替尼处理，可降低JAK2V617F细胞增殖并增加其死亡。相应地，在自噬或PP2A抑制剂协同作用下，鲁索替尼能显著抑制JAK2V617F驱动的MPN患者原代细胞（而非正常造血细胞）的增殖与克隆形成潜能。最终，与单用鲁索替尼相比，新型高效自噬抑制剂Lys05通过阻断鲁索替尼诱导的自噬，改善了小鼠白血病负荷的缓解效果并显著延长其总生存期。本研究表明，JAK2活性抑制介导的PP2A依赖性自噬是导致鲁索替尼耐药的重要因素。综上，我们的数据支持靶向自噬或其关键调控因子PP2A可增强JAK2V617F MPN细胞对鲁索替尼的敏感性，从而改善MPN患者的临床治疗。
肿瘤(癌症)患者之家