Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Hematology, Affiliated Hospital of the University of Nantong, Jiangsu, China.
Mol Oncol. 2017 Sep;11(9):1189-1207. doi: 10.1002/1878-0261.12088. Epub 2017 Jun 18.
Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK ) T-cell lymphoma is an aggressive neoplasm that is more commonly seen in children and young adults. The pathogenesis of NPM-ALK T-cell lymphoma is not completely understood. Wild-type ALK is a receptor tyrosine kinase that is physiologically expressed in neural tissues during early stages of human development, which suggests that ALK may interact with neurotrophic factors. The aberrant expression of NPM-ALK results from a translocation between the ALK gene on chromosome 2p23 and the NPM gene on chromosome 5q35. The nerve growth factor (NGF) is the first neurotrophic factor attributed to non-neural functions including cancer cell survival, proliferation, and metastasis. These functions are primarily mediated through the tropomyosin receptor kinase A (TrkA). The expression and role of NGF/TrkA in NPM-ALK T-cell lymphoma are not known. In this study, we tested the hypothesis that TrkA signaling is upregulated and sustains the survival of this lymphoma. Our data illustrate that TrkA and NGF are expressed in five NPM-ALK T-cell lymphoma cell lines and TrkA is expressed in 11 of 13 primary lymphoma tumors from patients. In addition, we found evidence to support that NPM-ALK and TrkA functionally interact. A selective TrkA inhibitor induced apoptosis and decreased cell viability, proliferation, and colony formation of NPM-ALK T-cell lymphoma cell lines. These effects were associated with downregulation of cell survival regulatory proteins. Similar results were also observed using specific knockdown of TrkA in NPM-ALK T-cell lymphoma cells by siRNA. Importantly, the inhibition of TrkA signaling was associated with antitumor effects in vivo, because tumor xenografts in mice regressed and the mice exhibited improved survival. In conclusion, TrkA plays an important role in the pathogenesis of NPM-ALK T-cell lymphoma, and therefore, targeting TrkA signaling may represent a novel approach to eradicate this aggressive neoplasm.
核磷蛋白-间变性淋巴瘤激酶阳性（NPM-ALK）T 细胞淋巴瘤是一种侵袭性肿瘤，更常见于儿童和年轻成人。NPM-ALK T 细胞淋巴瘤的发病机制尚不完全清楚。野生型 ALK 是一种受体酪氨酸激酶，在人类发育早期的神经组织中生理性表达，这表明 ALK 可能与神经营养因子相互作用。NPM-ALK 的异常表达是由于染色体 2p23 上的 ALK 基因与染色体 5q35 上的 NPM 基因之间的易位所致。神经生长因子（NGF）是第一个被认为具有非神经功能的神经营养因子，包括癌细胞的存活、增殖和转移。这些功能主要通过原肌球蛋白受体激酶 A（TrkA）介导。NGF/TrkA 在 NPM-ALK T 细胞淋巴瘤中的表达和作用尚不清楚。在这项研究中，我们检验了 TrkA 信号转导上调并维持这种淋巴瘤存活的假说。我们的数据表明，TrkA 和 NGF 在五种 NPM-ALK T 细胞淋巴瘤细胞系中表达，并且在 13 名患者的原发性淋巴瘤肿瘤中有 11 个表达 TrkA。此外，我们发现有证据支持 NPM-ALK 和 TrkA 具有功能相互作用。一种选择性的 TrkA 抑制剂诱导 NPM-ALK T 细胞淋巴瘤细胞系凋亡并降低细胞活力、增殖和集落形成。这些效应与细胞存活调节蛋白的下调有关。使用 siRNA 特异性敲低 NPM-ALK T 细胞淋巴瘤细胞中的 TrkA 也观察到类似的结果。重要的是，TrkA 信号转导的抑制与体内抗肿瘤作用相关，因为小鼠异种移植肿瘤消退，小鼠的存活得到改善。总之，TrkA 在 NPM-ALK T 细胞淋巴瘤的发病机制中起重要作用，因此，靶向 TrkA 信号转导可能代表消灭这种侵袭性肿瘤的新方法。
