TY - JOUR
T1 - Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma
AU - Singh, Rajesh R.
AU - Cho-Vega, 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
PY - 2009/3/15
Y1 - 2009/3/15
N2 - 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.
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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U2 - 10.1158/0008-5472.CAN-08-1808
DO - 10.1158/0008-5472.CAN-08-1808
M3 - Article
C2 - 19244133
AN - SCOPUS:65549154968
SN - 0008-5472
VL - 69
SP - 2550
EP - 2558
JO - Cancer Research
JF - Cancer Research
IS - 6
ER -