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Forum on Immunopathological Diseases and Therapeutics
SJR: 0.309 SNIP: 0.041 CiteScore™: 0.18

ISSN Imprimer: 2151-8017
ISSN En ligne: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v1.i1-2.50
pages 65-79

Rationale for Targeting of YY1 in Drug-resistant Leukemias

James A. McCubrey
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Stephen L. Abrams
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
William H. Chappell
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Linda S. Steelman
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Giovanni Ligresti
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Nadia Vella
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Andrea Marconi
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences; and Section of Occupational Medicine, Department of Internal Medicine, University of Catania, Italy
Lidia Proietti
Section of Occupational Medicine, Department of Internal Medicine, University of Catania, Italy
Ferdinando Nicoletti
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Massimo Libra
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Franca Stivala
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy

RÉSUMÉ

Cytokine-dependent, drug-sensitive, p53 wild-type (WT) FL5.12 cells and the doxorubicin-resistant derivative line (FL/Doxo) were used to determine the roles of the mechanisms by which p53 could alter Ying Yang 1 (YY1) transcription factor expression in early hematopoietic precursor cells. Drug resistance was associated with decreased p53 induction after doxorubicin treatment, which was caused by a higher level of proteosomal degradation of p53 and also resulted in a lower level of YY1 expression. Insertion of a dominant negative p53 gene further increased the resistance of the cells to chemotherapeutic drugs and also resulted in low levels of YY1 expression. Thus, in our system we could examine the effects of p53 and chemotherapeutic drugs on YY1 expression in a series of cells that were all derived from the common parental cell line. Doxorubicin increased the expression of the YY1 protein more in the parental cells, which have higher levels of WT p53, than in the doxorubicin-resistant cells. Thus, in our system of early hematopoietic cells YY1 expression was associated with functional p53 activity. In summary, our studies indicate that regulating YY1 activity may be a potential approach to regulate drug resistance.