Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia.
Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia.
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尽管急性髓系白血病 (AML) 的治疗已显着改善，但超过一半的患者会出现强化化疗难治性的疾病。功能基因组学方法提供了一种发现介导癌细胞异常生长和存活的特定分子的方法。因此，通过使用功能缺失的 RNA 干扰基因组筛选，我们发现肝细胞生长因子 (HGF) 的异常表达是 AML 发病机制的关键因素。我们发现，在所研究的近一半的 AML 细胞系和临床样本中，HGF 的表达导致其受体酪氨酸激酶 MET 的自分泌激活。 HGF 或 MET 的基因缺失可有效抑制表达 HGF 的 AML 细胞的生长和存活。然而，用特定 MET 激酶抑制剂克唑替尼治疗的白血病细胞由于 HGF 表达的代偿性上调而产生耐药性，导致 MET 信号传导恢复。在 AML 病例中，MET 与其他酪氨酸激酶（例如成纤维细胞生长因子受体 1 (FGFR1)）共同激活，同时抑制 FGFR1 和 MET 会阻断代偿性 HGF 上调，导致体外和体内异种移植模型中持续对数细胞杀伤。我们的结果证明了 AML 细胞对 MET 自分泌激活的广泛依赖性，以及 HGF 表达代偿性上调在维持该受体的白血病信号传导中的重要性。我们预计这些发现将导致设计额外的策略来阻止适应性细胞反应，这些反应驱动补偿性配体表达，作为人类癌症中致癌受体的靶向抑制的重要组成部分。
Although the treatment of acute myeloid leukemia (AML) has improved significantly, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified aberrant expression of the hepatocyte growth factor (HGF) as a critical factor in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance due to compensatory upregulation of HGF expression, leading to restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked compensatory HGF upregulation, resulting in sustained logarithmic cell kill both in vitro and in xenograft models in vivo. Our results demonstrate widespread dependence of AML cells on autocrine activation of MET, as well as the importance of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.
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