Sonic Hedgehog Signaling Pathway Is Activated in ALK-Positive Anaplastic Large Cell Lymphoma

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 6; pp. 2550 - 2558
• Main Authors: SINGH, Rajesh R, HEE CHO-VEGA, Jeong, VEGA, Francisco, DAVULURI, Yogesh, SHUGUANG MA, KASBIDI, Fatan, MILITO, Cristiane, LENNON, Patrick A, DRAKES, Elias, MEDEIROS, L. Jeffrey, LUTHRA, Rajyalakshmi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.03.2009
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Cycle - physiology; Cell Line, Tumor; Cell Survival - physiology; Enzyme Activation; Gene Amplification; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - biosynthesis; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hematologic and hematopoietic diseases; Humans; Immunohistochemistry; Jurkat Cells; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large-Cell, Anaplastic - enzymology; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - metabolism; Lymphoma, Large-Cell, Anaplastic - pathology; Medical sciences; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Protein-Tyrosine Kinases - biosynthesis; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptor Protein-Tyrosine Kinases; Signal Transduction; Transcription Factors - antagonists & inhibitors; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transfection; Tumors; Zinc Finger Protein GLI1; Signal transduction; Signaling pathway; Hedgehog protein; Lymphoproliferative syndrome; Ki1 positive large cell anaplastic lymphoma; Malignant hemopathy; Non Hodgkin lymphoma; Cell signaling; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-1808

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.