1. Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL.
- Author
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Decker S, Zirlik K, Djebatchie L, Hartmann D, Ihorst G, Schmitt-Graeff A, Herchenbach D, Jumaa H, Warmuth M, Veelken H, and Dierks C
- Subjects
- Aged, Aged, 80 and over, Antibodies, Monoclonal pharmacology, Antineoplastic Agents therapeutic use, Biomarkers blood, Biomarkers metabolism, Cells, Cultured, Drug Resistance, Neoplasm, Female, Hedgehog Proteins blood, Hedgehog Proteins metabolism, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Molecular Targeted Therapy, Patched Receptors, Patched-1 Receptor, Receptors, Cell Surface blood, Receptors, Cell Surface genetics, Receptors, G-Protein-Coupled antagonists & inhibitors, Signal Transduction drug effects, Smoothened Receptor, Stromal Cells drug effects, Stromal Cells metabolism, Stromal Cells pathology, Stromal Cells physiology, Transcription Factors blood, Transcription Factors genetics, Up-Regulation, Zinc Finger Protein GLI1, Chromosomes, Human, Pair 12 genetics, Hedgehog Proteins antagonists & inhibitors, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Receptors, Cell Surface metabolism, Transcription Factors metabolism, Trisomy genetics
- Abstract
Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HH-signaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high GLI1 and PTCH1 transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects.
- Published
- 2012
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