Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells

• Published in: Oncogene Vol. 29; no. 35; pp. 4885 - 4895
• Main Authors: DESCH, P, ASSLABER, D, ABERGER, F, HARTMANN, T. N, GREIL, R, KERN, D, SCHNIDAR, H, MANGELBERGER, D, ALINGER, B, STOECHER, M, HOFBAUER, S. W, NEUREITER, D, TINHOFER, I
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 02.09.2010
• Subjects: Ageing, cell death; Animals; Apoptosis; Apoptosis - drug effects; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biological and medical sciences; Cell Line, Tumor; Cell physiology; Cell proliferation; Cell survival; Cell Survival - drug effects; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell viability; Cellular biology; Cellular signal transduction; Chronic lymphocytic leukemia; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetic Predisposition to Disease; Health aspects; Hedgehog protein; Hedgehog Proteins - metabolism; Hematologic and hematopoietic diseases; Humans; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphatic leukemia; Lymphocytes; Lymphocytes B; Medical sciences; Molecular and cellular biology; Oncogene Proteins - antagonists & inhibitors; Oncogene Proteins - genetics; Physiological aspects; Pyridines - pharmacology; Pyrimidines - pharmacology; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - genetics; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-mediated interference; Signal transduction; Smoothened Receptor; Stromal cells; Trans-Activators - antagonists & inhibitors; Trans-Activators - genetics; Transcription; Transcription factors; Tumorigenesis; Veratrum Alkaloids - pharmacology; Zinc Finger Protein GLI1; Austria; Germany; Malignant hemopathy; Carcinogenesis; Cell signaling; GLI transcription factors; Chronic lymphocytic leukemia; hedgehog; stromal cells; Lymphoproliferative syndrome; Stromal cell; Inhibition; Transcription factor; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.243

The Hedgehog (Hh) pathway regulates cell proliferation and survival and contributes to tumorigenesis. We investigated the expression and function of this pathway in B-cell chronic lymphocytic leukemia (CLL) cells and in healthy B lymphocytes. Profiling of cognate Hh pathway members revealed reduced expression of two key Hh signaling effectors, Smoothened (SMOH) and GLI, in CLL cells, whereas transcription levels of other investigated members resembled normal B-lymphocyte levels. Examining the functional role of SMOH and GLI in cell survival, we found that CLL cells were hardly sensitive toward specific SMOH inhibition, but showed an unspecific decline in cell viability in response to high concentrations of the SMOH antagonist cyclopamine. In contrast, treatment with the novel GLI antagonist GANT61 reduced expression of the target gene Patched and preferentially decreased the viability of malignant cells. Specific RNA interference knockdown experiments in a CLL-derived cell line confirmed the autonomous role of GLI in malignant cell survival. GANT61-induced apoptosis in primary leukemic cells was partly attenuated by protective stromal cells, but not soluble sonic hedgehog ligand. In summary, our data show a downregulation of the classical Hh pathway in CLL and suggest an intrinsic SMOH-independent role of GLI in the ex vivo survival of CLL cells.