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

Rajesh R. Singh, Jeong Hee Cho, 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

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

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Anaplastic Large-Cell Lymphoma
Phosphatidylinositol 3-Kinase
HEK293 Cells
Tumor Cell Line
Hedgehog Proteins
anaplastic lymphoma kinase
Proteins
T-Cell Lymphoma
Gene Amplification
Protein-Tyrosine Kinases
Small Interfering RNA
Transfection
Cell Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. / Singh, Rajesh R.; Cho, Jeong Hee; Davuluri, Yogesh; Shuguang, Ma; Kasbidi, Fatan; Milito, Cristiane; Lennon, Patrick A.; Drakos, Elias; Medeiros, L. Jeffrey; Luthra, Rajyalakshmi; Vega, Francisco.

In: Cancer Research, Vol. 69, No. 6, 15.03.2009, p. 2550-2558.

Research output: Contribution to journalArticle

Singh, RR, Cho, JH, Davuluri, Y, Shuguang, M, Kasbidi, F, Milito, C, Lennon, PA, Drakos, E, Medeiros, LJ, Luthra, R & Vega, F 2009, 'Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma', Cancer Research, vol. 69, no. 6, pp. 2550-2558. https://doi.org/10.1158/0008-5472.CAN-08-1808
Singh, Rajesh R. ; Cho, Jeong Hee ; Davuluri, Yogesh ; Shuguang, Ma ; Kasbidi, Fatan ; Milito, Cristiane ; Lennon, Patrick A. ; Drakos, Elias ; Medeiros, L. Jeffrey ; Luthra, Rajyalakshmi ; Vega, Francisco. / Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. In: Cancer Research. 2009 ; Vol. 69, No. 6. pp. 2550-2558.
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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.",
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AU - Cho, Jeong Hee

AU - Davuluri, Yogesh

AU - Shuguang, Ma

AU - Kasbidi, Fatan

AU - Milito, Cristiane

AU - Lennon, Patrick A.

AU - Drakos, Elias

AU - Medeiros, L. Jeffrey

AU - Luthra, Rajyalakshmi

AU - Vega, Francisco

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AB - 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.

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