CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Nat Chem Biol. 2012 Jan 29;8(3):285-93. doi: 10.1038/nchembio.775.
Constitutive activation of STAT5 is critical for the maintenance of chronic myeloid leukemia (CML) characterized by the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (TKIs) for the STAT5-activating kinase JAK2 have been discussed as a treatment option for CML patients. Using murine leukemia models combined with inducible ablation of JAK2, we show JAK2 dependence for initial lymphoid transformation, which is lost once leukemia is established. In contrast, initial myeloid transformation and leukemia maintenance were independent of JAK2. Nevertheless, several JAK2 TKIs induced apoptosis in BCR-ABL(+) cells irrespective of the presence of JAK2. This is caused by the previously unknown direct 'off-target' inhibition of BCR-ABL. Cellular and enzymatic analyses suggest that BCR-ABL phosphorylates STAT5 directly. Our findings suggest uncoupling of the canonical JAK2-STAT5 module upon BCR-ABL expression, thereby making JAK2 targeting dispensable. Thus, attempts to pharmacologically target STAT5 in BCR-ABL(+) diseases need to focus on STAT5 itself.
STAT5 的组成性激活对于以 BCR-ABL 癌蛋白为特征的慢性髓系白血病 (CML) 的维持至关重要。已经讨论了针对激活 STAT5 的激酶 JAK2 的酪氨酸激酶抑制剂 (TKI) 作为 CML 患者的治疗选择。我们使用结合 JAK2 诱导性缺失的小鼠白血病模型表明，JAK2 依赖于初始淋巴样转化，一旦白血病建立，这种依赖就会丢失。相比之下，初始髓样转化和白血病维持与 JAK2 无关。然而，几种 JAK2 TKI 诱导 BCR-ABL(+)细胞凋亡，而与 JAK2 的存在与否无关。这是由于先前未知的 BCR-ABL 的直接“脱靶”抑制。细胞和酶分析表明，BCR-ABL 直接磷酸化 STAT5。我们的研究结果表明，BCR-ABL 表达后，经典的 JAK2-STAT5 模块被解偶联，从而使 JAK2 靶向变得可有可无。因此，在 BCR-ABL(+)疾病中尝试药理学靶向 STAT5 需要专注于 STAT5 本身。
