Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
Int J Cancer. 2011 Nov 15;129(10):2512-21. doi: 10.1002/ijc.25910. Epub 2011 Apr 8.
Our study determined if Janus kinase 2 (JAK2) was activated in acute myelogenous leukemia (AML; n = 77, excluding acute promyelocytic leukemia) by immunohistochemistry (IHC) using a phosphor-specific antibody against JAK2. p-JAK2 was detectable in all cases, although its levels varied between patient samples (high levels, n = 31; low levels, n = 46). The quantification of levels of p-JAK2 by IHC was well correlated with that assessed by Western blot analyses and fluorescence-activated cell sorting (FACS). Levels of p-JAK2 were directly correlated with high white blood cell count (52.3 × 10(3) /L in patients with high p-JAK2 vs. 28.3 × 10(3) /L in patients with low p-JAK2, p < 0.01) and were inversely correlated with complete remission rates (45% in patients with high p-JAK2 vs. 78% in patients with low p-JAK2, p < 0.003). In addition, multivariate analysis confirmed that high levels of p-JAK2 remained a significant factor for overall survival (hazard ratio = 2.213; 95% confidence interval, 1.212-4.041, p = 0.023). Moreover, we found that AZ960, a novel and specific inhibitor of the JAK2 kinase, potently inhibited the clonogenic growth and induced apoptosis of freshly isolated AML cells from patients in association with cleavage of caspase 3 and downregulation of anti-apoptotic Bcl-xL proteins. Taken together, JAK2 may be a promising molecular target for treatment of AML.
我们的研究通过使用针对 JAK2 的磷酸化特异性抗体进行免疫组织化学（IHC）来确定急性髓细胞性白血病（AML；n = 77，不包括急性早幼粒细胞白血病）中是否激活了 Janus 激酶 2（JAK2）。p-JAK2 在所有病例中均可检测到，尽管其水平在患者样本之间有所不同（高水平，n = 31；低水平，n = 46）。通过 IHC 定量测定 p-JAK2 的水平与通过 Western blot 分析和荧光激活细胞分选（FACS）评估的水平高度相关。p-JAK2 的水平与高白细胞计数直接相关（高 p-JAK2 患者为 52.3×10^3/L，低 p-JAK2 患者为 28.3×10^3/L，p<0.01），与完全缓解率呈负相关（高 p-JAK2 患者为 45%，低 p-JAK2 患者为 78%，p<0.003）。此外，多变量分析证实，高水平的 p-JAK2 仍然是总生存的重要因素（危险比=2.213；95%置信区间，1.212-4.041，p = 0.023）。此外，我们发现 AZ960，一种新型和特异性的 JAK2 激酶抑制剂，可有效抑制来自患者的新鲜分离的 AML 细胞的集落生长并诱导细胞凋亡，同时伴有 caspase 3 的裂解和抗凋亡 Bcl-xL 蛋白的下调。综上所述，JAK2 可能是治疗 AML 的有前途的分子靶标。
