Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Exp Hematol. 2012 May;40(5):418-27. doi: 10.1016/j.exphem.2012.01.003. Epub 2012 Jan 10.
Sonic hedgehog (Shh) signaling plays an important role in many human cancers and cancer stem cells. Here we investigate the activity and functional role of Shh signaling in chronic myeloid leukemia (CML) and leukemia progenitor cells. Differential activation of Shh signaling was found in about 50% CML chronic phase samples, about 70% of CML accelerated phase samples, and >80% CML blast crisis phase samples. Deregulated activation of Shh signaling was observed in CD34(+) and c-kit(+) leukemia progenitor cells. Stimulation of Shh signaling with exogenous Shh peptide induced expansion of CD34(+) and c-kit(+) progenitor cells (p < 0.05), inversely, blocking the pathway with signal inhibitor induced cell apoptosis (p < 0.05). Low level of Shh protein was observed in CML bone marrow stromal cells, and CD34(+) progenitor cells are less sensitive to exogenous Shh peptide and more sensitive to cyclopamine than CD34(-) cells (p < 0.05), implying cell-autonomous activation of Shh signaling play a predominant role in progenitor cells. Coactivation of Shh and β-catenin signaling was found in CD34(+) and c-kit(+) progenitor cells. Administration of Shh-neutralizing antibody or Wnt3a-neutralizing antibody in c-kit(+) progenitor cells induced cell apoptosis; however, Wnt3a peptide could salvage cell apoptosis, while Shh peptide failed to revert anti-Wnt3a-induced cell apoptosis. C-MYC, GLI1, BCL-2, and P21 were also found to be downstream targets of Shh signaling, mediating apoptosis or G(2)/M cell cycle arrest of progenitor cells. Our results demonstrate that autoactivated Shh signaling provides survival and proliferative cues in CML progenitor cells through downstream β-catenin signaling, suggesting a novel therapeutic approach in CML.
Sonic hedgehog (Shh) 信号在许多人类癌症和癌症干细胞中发挥着重要作用。在这里，我们研究了 Shh 信号在慢性髓性白血病 (CML) 和白血病祖细胞中的活性和功能作用。在大约 50%的 CML 慢性期样本、约 70%的 CML 加速期样本和 >80%的 CML 急变期样本中发现 Shh 信号的差异激活。在 CD34(+)和 c-kit(+)白血病祖细胞中观察到 Shh 信号的失调激活。用外源性 Shh 肽刺激 Shh 信号诱导 CD34(+)和 c-kit(+)祖细胞的扩增(p<0.05)，相反，用信号抑制剂阻断通路诱导细胞凋亡(p<0.05)。在 CML 骨髓基质细胞中观察到低水平的 Shh 蛋白，CD34(+)祖细胞对外源性 Shh 肽的敏感性低于 CD34(-)细胞，对 cyclopamine 的敏感性更高(p<0.05)，这表明 Shh 信号的细胞自主激活在祖细胞中发挥主要作用。在 CD34(+)和 c-kit(+)祖细胞中发现了 Shh 和 β-catenin 信号的共激活。在 c-kit(+)祖细胞中给予 Shh 中和抗体或 Wnt3a 中和抗体可诱导细胞凋亡；然而，Wnt3a 肽可以挽救细胞凋亡，而 Shh 肽不能逆转抗 Wnt3a 诱导的细胞凋亡。还发现 C-MYC、GLI1、BCL-2 和 P21 是 Shh 信号的下游靶标，介导祖细胞的凋亡或 G2/M 细胞周期停滞。我们的结果表明，自动激活的 Shh 信号通过下游的 β-catenin 信号为 CML 祖细胞提供生存和增殖信号，提示了一种治疗 CML 的新方法。
