Department of Pathology, Stanford University School of Medicine, Stanford Hospital and Clinics, Stanford, CA 94305, USA.
Leukemia. 2012 Apr;26(4):720-7. doi: 10.1038/leu.2011.261. Epub 2011 Oct 18.
About 10% of patients with essential thrombocythemia (ET) or myelofibrosis (MF) that lack mutations in JAK2 harbor an activating mutation in the thrombopoietin receptor, MPLW515L. Distinct from the JAK2V617F retroviral transplant model, the MPLW515L model recapitulates many features of ET and MF, including severe fibrosis and thrombocytosis. We have tested EXEL-8232, an experimental potent JAK2 inhibitor, for efficacy in suppression of thrombocytosis in vivo and for its ability to attenuate MPLW515L myeloproliferative disease. EXEL-8232 was administered for 28 days q12 h by oral gavage at doses of 30 or 100 mg/kg, prospectively. Animals treated with EXEL-8232 at 100 mg/kg had normalized high platelet counts, eliminated extramedullary hematopoiesis in the spleen and eliminated bone marrow fibrosis, whereas the wild-type controls did not develop thrombocytopenia. Consistent with a clinical response in this model, we validated surrogate end points for response to treatment, including a reduction of endogenous colony growth and signaling inhibition in immature erythroid and myeloid primary cells both in vitro and upon treatment in vivo. We conclude that EXEL-8232 has efficacy in treatment of thrombocytosis in vivo in a murine model of ET and MF, and may be of therapeutic benefit for patients with MPL-mutant MPN.
约 10%的原发性血小板增多症 (ET) 或骨髓纤维化 (MF) 患者缺乏 JAK2 突变，存在血小板生成素受体 MPLW515L 的激活突变。与 JAK2V617F 逆转录病毒移植模型不同，MPLW515L 模型再现了 ET 和 MF 的许多特征，包括严重纤维化和血小板增多。我们已经测试了 EXEL-8232，一种实验性强效 JAK2 抑制剂，以评估其在体内抑制血小板增多症的疗效及其减轻 MPLW515L 骨髓增生性疾病的能力。EXEL-8232 通过口服灌胃以 30 或 100mg/kg 的剂量每 12 小时给药 1 次，共给药 28 天。用 100mg/kg EXEL-8232 治疗的动物血小板计数正常化，消除脾脏中的骨髓外造血并消除骨髓纤维化，而野生型对照动物未出现血小板减少症。与该模型中的临床反应一致，我们验证了治疗反应的替代终点，包括减少体内和体内治疗后幼稚红细胞和髓样原代细胞中的内源性集落生长和信号抑制。我们得出结论，EXEL-8232 对 ET 和 MF 小鼠模型中的体内血小板增多症具有疗效，并且可能对 MPL 突变的 MPN 患者具有治疗益处。
