title: Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma.
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/GLI1 signaling pathway is activated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). We show that SHH, but not its transcriptional effector GLI1, is amplified in ALK+ ALCL tumors and cell lines, and that SHH and GLI1 proteins are highly expressed in ALK+ ALCL tumors and cell lines. We also show that inhibition of SHH/GLI1 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/GLI1 signaling as shown by increase of CCND2 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 GSK3beta 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.
authors.affiliation: Department of Hematopathology and School of Health Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Singh
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Cho-Vega
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Davuluri
authors.forename: Shuguang
authors.initials: S
authors.lastname: Ma
authors.forename: Fatan
authors.initials: F
authors.lastname: Kasbidi
authors.forename: Cristiane
authors.initials: C
authors.lastname: Milito
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lennon
authors.forename: Elias
authors.initials: E
authors.lastname: Drakos
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation; D005784:Gene Amplification; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D019869:Phosphatidylinositol 3-Kinases; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt