TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK ⁺ T‐cell lymphoma

Abstract

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 si RNA. 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.