Pomicter Anthony D, Eiring Anna M, Senina Anna V, Zabriskie Matthew S, Marvin James E, Prchal Josef T, O'Hare Thomas, Deininger Michael W
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Flow Cytometry Shared Resource, University of Utah, Salt Lake City, UT, USA.
Exp Hematol. 2015 Jul;43(7):537-45.e1-11. doi: 10.1016/j.exphem.2015.03.006. Epub 2015 Apr 24.
Activation of Janus kinase 2 (JAK2), frequently as a result of the JAK2(V617F) mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and myelofibrosis, and it is thought to be responsible for the constitutional symptoms associated with these diseases. BMS-911543 is a JAK2-selective inhibitor that induces apoptosis in JAK2-dependent cell lines and inhibits the growth of CD34(+) progenitor cells from patients with JAK2(V617F)-positive MPN. To explore the clinical potential of this inhibitor, we tested BMS-911543 in a murine retroviral transduction-transplantation model of JAK2(V617F) MPN. Treatment was initiated at two dose levels (3 mg/kg and 10 mg/kg) when the hematocrit exceeded 70%. Following the first week, white blood cell counts were reduced to normal in the high-dose group and were maintained well below the levels in vehicle-treated mice throughout the study. However, BMS-911543 had no effect on red blood cell parameters. After 42 days of treatment, the proportion of JAK2(V617F)-positive cells in hematopoietic tissues was identical or slightly increased compared with controls. Plasma concentrations of interleukin 6, interleukin 15, and tumor necrosis factor α were elevated in MPN mice and reduced in the high-dose treatment group, whereas other cytokines were unchanged. Inhibitor activity after dosing was confirmed in a cell culture assay using the plasma of dosed mice and phosphorylated signal transducer and activator of transcription 5 flow cytometry. Collectively, these results show that BMS-911543 has limited activity in this murine model of JAK2(V617F)-driven MPN and suggest that targeting JAK2 alone may be insufficient to achieve effective disease control.
Janus激酶2（JAK2）的激活，通常是JAK2（V617F）突变的结果，是经典骨髓增殖性肿瘤（MPN）真性红细胞增多症、原发性血小板增多症和骨髓纤维化的一个特征，并且被认为与这些疾病相关的全身症状有关。BMS-911543是一种JAK2选择性抑制剂，可诱导JAK2依赖的细胞系凋亡，并抑制JAK2（V617F）阳性MPN患者的CD34（+）祖细胞生长。为了探索这种抑制剂的临床潜力，我们在JAK2（V617F）MPN的小鼠逆转录病毒转导-移植模型中测试了BMS-911543。当血细胞比容超过70%时，以两种剂量水平（3mg/kg和10mg/kg）开始治疗。在第一周后，高剂量组的白细胞计数降至正常水平，并且在整个研究过程中一直维持在低于载体处理小鼠的水平。然而，BMS-911543对红细胞参数没有影响。治疗42天后，造血组织中JAK2（V617F）阳性细胞的比例与对照组相同或略有增加。MPN小鼠血浆中白细胞介素6、白细胞介素15和肿瘤坏死因子α浓度升高，而高剂量治疗组降低，而其他细胞因子没有变化。使用给药小鼠的血浆和磷酸化信号转导及转录激活因子5流式细胞术在细胞培养试验中证实了给药后的抑制剂活性。总体而言，这些结果表明BMS-911543在这个JAK2（V617F）驱动的MPN小鼠模型中的活性有限，并表明仅靶向JAK2可能不足以实现有效的疾病控制。
