Resistance to chemotherapeutic agents remains one of the major impediments to a successful treatment of chronic myeloid leukemia (CML). Misregulation of the activity of a specific group of ATP-binding cassette transporters (ABC) is responsible for reducing the intracellular concentration of drugs in leukemic cells. Moreover, a consistent body of evidence also suggests that ABC transporters play a role in cancer progression beyond the efflux of cytotoxic drugs. Despite a large number of studies that investigated the function of the ABC transporters, little is known about the transcriptional regulation of the ABC genes. Here, we present data showing that the oncoprotein c-MYC is a direct transcriptional regulator of a large set of ABC transporters in CML. Furthermore, molecular analysis carried out in CD34+ hematopoietic cell precursors of 21 CML patients reveals that the overexpression of ABC transporters driven by c-MYC is a peculiar characteristic of the CD34+ population in CML and was not found either in the population of mononuclear cells from which they had been purified nor in CD34+ cells isolated from healthy donors. Finally, we describe how the methylation state of CpG islands may regulate the access of c-MYC to ABCG2 gene promoter, a well-studied gene associated with multidrug resistance in CML, hence affecting its expression. Taken together, our findings support a model in which c-MYC-driven transcriptional events, combined with epigenetic mechanisms, direct and regulate the expression of ABC genes, with possible implications in tumor malignancy and drug efflux in CML.

c-MYC oncoprotein dictates transcriptional profiles of ATP-binding cassette transporter genes in Chronic Myelogenous Leukemia CD34+ hematopoietic progenitor cells

PORRO, ANTONIO;SOVERINI, SIMONA;DIOLAITI, DANIEL;GHERARDI, SAMUELE;TERRAGNA, CAROLINA;DURANTE, SANDRA;VALLI, EMANUELE;BERNARDONI, ROBERTO;BACCARANI, MICHELE;MARTINELLI, GIOVANNI;PERINI, GIOVANNI
2011

Abstract

Resistance to chemotherapeutic agents remains one of the major impediments to a successful treatment of chronic myeloid leukemia (CML). Misregulation of the activity of a specific group of ATP-binding cassette transporters (ABC) is responsible for reducing the intracellular concentration of drugs in leukemic cells. Moreover, a consistent body of evidence also suggests that ABC transporters play a role in cancer progression beyond the efflux of cytotoxic drugs. Despite a large number of studies that investigated the function of the ABC transporters, little is known about the transcriptional regulation of the ABC genes. Here, we present data showing that the oncoprotein c-MYC is a direct transcriptional regulator of a large set of ABC transporters in CML. Furthermore, molecular analysis carried out in CD34+ hematopoietic cell precursors of 21 CML patients reveals that the overexpression of ABC transporters driven by c-MYC is a peculiar characteristic of the CD34+ population in CML and was not found either in the population of mononuclear cells from which they had been purified nor in CD34+ cells isolated from healthy donors. Finally, we describe how the methylation state of CpG islands may regulate the access of c-MYC to ABCG2 gene promoter, a well-studied gene associated with multidrug resistance in CML, hence affecting its expression. Taken together, our findings support a model in which c-MYC-driven transcriptional events, combined with epigenetic mechanisms, direct and regulate the expression of ABC genes, with possible implications in tumor malignancy and drug efflux in CML.
A. Porro; N. Iraci; S. Soverini; D. Diolaiti; S. Gherardi; C. Terragna; S. Durante; E. Valli; T. Kalebic; R. Bernardoni; C. Perrod; M. Haber; M.D. Norris; M. Baccarani; G. Martinelli; G. Perini
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/103157
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