GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML
GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML
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DOI：
10.1182/blood-2016-05-718585
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发表时间：
2017-06-29
期刊：
影响因子：
20.3
通讯作者：
Merchant, Akil A.
中科院分区：
文献类型：
--
作者：
Chaudhry, Parvesh;Singh, Mohan;Merchant, Akil A.
Hedgehog (Hh) 信号通路在许多癌症中被激活，是治疗开发的一个有希望的靶点。据报道，在基底细胞癌和髓母细胞瘤中存在 Patched 受体 (PTCH) 缺失或 Smoothened (SMO) 激活突变，但在大多数肿瘤类型中基本上不存在。因此，大多数癌症（包括血液恶性肿瘤）中通路激活的机制仍然未知。在正常组织中，通过 PTCH/SMO 激活 Hh 通路会导致下游转录激活因子 GLI1 增加和 GLI3 转录抑制因子 (GLI3R) 减少。在本文中，我们证实 Hh 通路在急性髓系白血病 (AML) 中具有活性，然而，这种活性在很大程度上独立于 SMO。对癌症基因组图谱 AML 数据集的表观遗传学和基因表达分析表明，大多数 AML 患者样本中 GLI3 表达被沉默，并且 GLI3 基因座异常甲基化。我们表明，GLI3R 是 SMO 拮抗剂在 AML 样本中发挥治疗作用所必需的，并且 GLI3R 的恢复可抑制 AML 的生长。我们还证明 GLI3R 通过下调 AKT 表达来抑制 AML 生长。总之，这项研究提供了第一个证据，证明 GLI3R 在 AML 中不依赖于 SMO 的 Hh 信号传导中发挥着重要作用，并表明 GLI3R 可以作为 SMO 拮抗剂临床试验中患者选择的潜在生物标志物。此外，这些数据支持临床试验中低甲基化药物与SMO拮抗剂的合理组合。
The Hedgehog (Hh) signaling pathway is activated in many cancers and is a promising target for therapeutic development. Deletions in the receptor Patched (PTCH) or activating mutations in Smoothened (SMO) have been reported in basal cell carcinoma and medulloblastoma, but are largely absent in most tumor types. Therefore, the mechanism of pathway activation in most cancers, including hematological malignancies, remains unknown. In normal tissues, Hh pathway activation via PTCH/SMO causes an increase in the downstream transcriptional activator GLI1 and a decrease in the GLI3 transcriptional repressor (GLI3R). In this article, we confirm that the Hh pathway is active in acute myeloid leukemia (AML), however, this activity is largely independent of SMO. Epigenetic and gene expression analysis of The Cancer Genome Atlas AML data set reveals that GLI3 expression is silenced in most AML patient samples, and the GLI3 locus is abnormally methylated. We show that GLI3R is required for the therapeutic effect of SMO antagonists in AML samples and restoration of GLI3R suppresses the growth of AML. We additionally demonstrate that GLI3R represses AML growth by downregulating AKT expression. In summary, this study provides the first evidence that GLI3R plays an essential role in SMO-independent Hh signaling in AML, and suggests that GLI3R could serve as a potential biomarker for patient selection in SMO antagonist clinical trials. Furthermore, these data support rational combinations of hypomethylating agents with SMO antagonists in clinical trials.