title: Elevated levels of STAT1 in Fanconi anemia group A lymphoblasts correlate with the cells' sensitivity to DNA interstrand crosslinking drugs.
abstract: Progressive bone marrow failure starting in the first decade of life is one of the main characteristics of Fanconi anemia. Along with the bone marrow failure, this pathology is characterized by congenital malformations, endocrine dysfunction and an extraordinary predisposition to develop cancer. The fact that hematopoietic progenitor cells from subjects with Fanconi anemia are sensitive to both DNA-interstrand crosslinking agents and inflammatory cytokines, which are aberrantly overproduced in these patients, has led to different explanations for the causes of the bone marrow failure. We analyzed STAT1 expression in lymphoblastoid cell lines derived from patients with Fanconi anemia group A and correlated this with aspects of the Fanconi anemia phenotype such as sensitivity to genotoxic agents or to inhibitory cytokines. We provide evidence of overexpression of STAT1 in FANCA-deficient cells which has both transcriptional and post-translational components, and is related to the constitutive activation of ERK in Fanconi anemia group A cells, since it can be reverted by treatment with U0126. STAT1 phosphorylation was not defective in the lymphoblasts, so these cells accumulated higher levels of active STAT1 in response to interferon gamma, probably in relation to their greater sensitivity to this cytokine. On the other hand, inhibition of STAT1 by genetic or chemical means reverted the hypersensitivity of Fanconi anemia group A lymphoblasts to DNA interstrand crosslinking agents. Our data provide an explanation for the mixed sensitivity of Fanconi anemia group A cells to both genotoxic stress and inflammatory cytokines and indicate new targets for the treatment of bone marrow failure in these patients.
authors.affiliation: Servicio de Hematología, Instituto de Formación e Investigación Marqués de Valdecilla-IFIMAV, Santander, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Prieto-Remón
authors.forename: Dámaso
authors.initials: D
authors.lastname: Sánchez-Carrera
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Duarte
authors.forename: Carlos
authors.initials: C
authors.lastname: Richard
authors.forename: Carlos
authors.initials: C
authors.lastname: Pipaón
mesh_terms: D002460:Cell Line; D003432:Cross-Linking Reagents / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004351:Drug Resistance / Q000235:genetics; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism*; D052217:Fanconi Anemia Complementation Group A Protein / Q000172:deficiency / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D054503:Lymphoid Progenitor Cells / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D003432:Cross-Linking Reagents; D052217:Fanconi Anemia Complementation Group A Protein; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases