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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Antibodies, Monoclonal / pharmacology
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Antineoplastic Agents / therapeutic use
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Biomarkers / blood
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Biomarkers / metabolism
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Cells, Cultured
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Chromosomes, Human, Pair 12 / genetics*
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Drug Resistance, Neoplasm
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Female
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Hedgehog Proteins / antagonists & inhibitors*
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Hedgehog Proteins / blood
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Hedgehog Proteins / metabolism
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Male
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Middle Aged
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Molecular Targeted Therapy
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Patched Receptors
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Patched-1 Receptor
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Receptors, Cell Surface / blood
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Signal Transduction / drug effects
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Smoothened Receptor
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Stromal Cells / drug effects
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Stromal Cells / metabolism
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Stromal Cells / pathology
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Stromal Cells / physiology
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Transcription Factors / blood
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Trisomy / genetics*
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Up-Regulation
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Zinc Finger Protein GLI1
Substances
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Antibodies, Monoclonal
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Antineoplastic Agents
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Biomarkers
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DHH protein, human
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GLI1 protein, human
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Hedgehog Proteins
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PTCH1 protein, human
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Patched Receptors
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Patched-1 Receptor
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Receptors, Cell Surface
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Receptors, G-Protein-Coupled
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SMO protein, human
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Smoothened Receptor
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Transcription Factors
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Zinc Finger Protein GLI1