Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma

Rajesh R. Singh, Jeong Hee Cho-Vega, Yogesh Davuluri, Ma Shuguang, Fatan Kasbidi, Cristiane Milito, Patrick A. Lennon, Elias Drakos, L. Jeffrey Medeiros, Rajyalakshmi Luthra, Francisco Vega

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Deregulation of the sonic hedgehog (SHH) signaling pathway has been implicated in several cancers but has not been explored in T-cell lymphomas. Here, we report that the SHH/ GLU signaling pathway is activated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). We show that SHH, but not its transcriptional effector GLU, is amplified in ALK+ ALCL tumors and cell lines, and that SHH and GLU proteins are highly expressed in ALK+ ALCL tumors and cell lines. We also show that inhibition of SHH/GLU signaling with cyclopamine-KAAD, as well as silencing GLI1 gene expression by small interfering (si)RNA, decreased cell viability and clonogenicity of ALK+ ALCL cells. Transfection of wild-type or mutant NPM-ALK into 293T cells showed that only wild-type NPM-ALK increased GLI1 protein levels and activated SHH/GLU signaling as shown by increase of CCSD2 mRNA levels. Inhibition of ALK tyrosine kinase and phosphatidylinositol 3-kinase (PI3K)/AKT or forced expression of pAKT down-regulated or up-regulated SHH/GLI1 signaling, respectively. Inhibition of GSK33 in 293T cells also increased protein levels of GLI1. In conclusion, the SHH/GLI1 signaling pathway is activated in ALK+ ALCL. SHH/GLI1 activation is the result of SHH gene amplification and is further mediated by NPM-ALK through activation of PI3K/AKT and stabilization of GLI1 protein. There is a positive synergistic effect between the SHH/GLI1 and PI3K/AKT pathways that contributes to the lymphomagenic effect of NPM-ALK.

Original languageEnglish (US)
Pages (from-to)2550-2558
Number of pages9
JournalCancer Research
Volume69
Issue number6
DOIs
StatePublished - Mar 15 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Singh, R. R., Cho-Vega, J. H., Davuluri, Y., Shuguang, M., Kasbidi, F., Milito, C., Lennon, P. A., Drakos, E., Medeiros, L. J., Luthra, R., & Vega, F. (2009). Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. Cancer Research, 69(6), 2550-2558. https://doi.org/10.1158/0008-5472.CAN-08-1808