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1. Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers

Author

Massimo D'Amico, Dario Campana, Marinella Veltroni, Emanuele Cilia, Olivia Crociani, Andrea Becchetti, Annarosa Arcangeli, Serena Pillozzi, Amedeo Amedei, Emanuele De Lorenzo, Giuseppe Basso, Benedetta Accordi, Marika Masselli, Pillozzi, S, Masselli, M, De Lorenzo, E, Accordi, B, Cilia, E, Crociani, O, Amedei, A, Veltroni, M, D'Amico, M, Basso, G, Becchetti, A, Campana, D, and Arcangeli, A

Subjects
Receptors, CXCR4, ALL, ERG, potassium channels, doxorubicine, chemotherapeutics, Pyridines, Blotting, Western, Immunology, Antineoplastic Agents, Mice, SCID, Biochemistry, Mice, Chemokine receptor, Piperidines, BIO/09 - FISIOLOGIA, Mice, Inbred NOD, Acute lymphocytic leukemia, Potassium Channel Blockers, Tumor Cells, Cultured, medicine, Animals, Humans, Protein kinase B, Cells, Cultured, PI3K/AKT/mTOR pathway, business.industry, Integrin beta1, Lymphoblast, Cell Membrane, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Xenograft Model Antitumor Assays, Coculture Techniques, Ether-A-Go-Go Potassium Channels, medicine.anatomical_structure, Doxorubicin, Drug Resistance, Neoplasm, Multiprotein Complexes, Cancer research, Prednisone, Female, RNA Interference, Bone marrow, Signal transduction, business, Signal Transduction
Abstract

Bone marrow mesenchymal cells (MSCs) can protect leukemic cells from chemotherapy, thus increasing their survival rate. We studied the potential molecular mechanisms underlying this effect in acute lymphoblastic leukemia (ALL) cells. Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1 (human ether-à-go-go-related gene 1) channels, the β1-integrin subunit, and the chemokine receptor CXC chemokine receptor-4. The assembly of such a protein complex activated both the extracellular signal-related kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/Akt prosurvival signaling pathways. At the same time, ALL cells became markedly resistant to chemotherapy-induced apoptosis. hERG1 channel function appeared to be important for both the initiation of prosurvival signals and the development of drug resistance, because specific channel blockers decreased the protective effect of MSCs. NOD/SCID mice engrafted with ALL cells and treated with channel blockers showed reduced leukemic infiltration and had higher survival rates. Moreover, hERG1 blockade enhanced the therapeutic effect produced by corticosteroids. Our findings provide a rationale for clinical testing of hERG1 blockers in the context of antileukemic therapy for patients with ALL.

Published
2011

2. Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers.

Author

Pillozzi S, Masselli M, De Lorenzo E, Accordi B, Cilia E, Crociani O, Amedei A, Veltroni M, D'Amico M, Basso G, Becchetti A, Campana D, and Arcangeli A

Subjects
Animals, Blotting, Western, Cell Membrane metabolism, Cells, Cultured, Coculture Techniques, Doxorubicin pharmacology, Ether-A-Go-Go Potassium Channels genetics, Ether-A-Go-Go Potassium Channels metabolism, Female, Humans, Integrin beta1 metabolism, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Multiprotein Complexes metabolism, Piperidines pharmacology, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prednisone pharmacology, Pyridines pharmacology, RNA Interference, Receptors, CXCR4 metabolism, Signal Transduction drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Potassium Channel Blockers pharmacology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Abstract

Bone marrow mesenchymal cells (MSCs) can protect leukemic cells from chemotherapy, thus increasing their survival rate. We studied the potential molecular mechanisms underlying this effect in acute lymphoblastic leukemia (ALL) cells. Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1 (human ether-à-go-go-related gene 1) channels, the β(1)-integrin subunit, and the chemokine receptor CXC chemokine receptor-4. The assembly of such a protein complex activated both the extracellular signal-related kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/Akt prosurvival signaling pathways. At the same time, ALL cells became markedly resistant to chemotherapy-induced apoptosis. hERG1 channel function appeared to be important for both the initiation of prosurvival signals and the development of drug resistance, because specific channel blockers decreased the protective effect of MSCs. NOD/SCID mice engrafted with ALL cells and treated with channel blockers showed reduced leukemic infiltration and had higher survival rates. Moreover, hERG1 blockade enhanced the therapeutic effect produced by corticosteroids. Our findings provide a rationale for clinical testing of hERG1 blockers in the context of antileukemic therapy for patients with ALL.

Published
2011
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