{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T04:35:07Z","timestamp":1761712507106,"version":"build-2065373602"},"reference-count":32,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2017,4,3]],"date-time":"2017-04-03T00:00:00Z","timestamp":1491177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005774","name":"Universitat de Barcelona","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    While working with G418\u2010resistant stably transfected cells, we realized the neomycin resistance (NeoR) gene, which encodes the aminoglycoside\u20103'\u2010phosphotransferase\u2010IIa [APH(3')\u2010IIa], also confers resistance to the nucleoside analog fludarabine. Fludarabine is a cytostatic drug widely used in the treatment of hematologic and solid tumors, as well as in the conditioning of patients before transplantation of hematopoietic progenitors. We present evidence that NeoR\u2010transfected cells do not incorporate fludarabine, thus avoiding DNA damage caused by the drug, evidenced by a lack of FANCD2 monoubiquitination and impaired apoptosis. A screening of other nucleoside analogs revealed that APH(3')\u2010IIa only protects against ATP purine analogs. Moreover, APH(3')\u2010IIa ATPase activity is inhibited by fludarabine monophosphate, suggesting that APH(3')\u2010IIa blocks fludarabine incorporation into DNA by dephosphorylating its active fludarabine triphosphate form. Furthermore, overexpression of the catalytic subunit of the eukaryotic kinase PKA, which is structurally related to APHs, also provides resistance to fludarabine, anticipating its putative utility as a response marker to the drug. Our results preclude the use of Neo marker plasmids in the study of purine analogs and unveils a new resistance mechanism against these chemotherapeuticals.\u2014S\u00e1nchez\u2010Carrera, D., Bravo\u2010Navas, S., Cabez\u00f3n, E., Arechaga, I., Cabezas, M., Y\u00e1\u00f1ez, L., Pipa\u00f3n, C. Fludarabine resistance mediated by aminoglycoside\u20103'\u2010phosphotransferase\u2010IIa and the structurally related eukaryotic cAMP\u2010dependent protein kinase. FASEB J. 31, 3007\u20133017 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201601245r","type":"journal-article","created":{"date-parts":[[2017,4,3]],"date-time":"2017-04-03T20:53:22Z","timestamp":1491252802000},"page":"3007-3017","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fludarabine resistance mediated by aminoglycoside\u20103'phosphotransferase\u2010IIa and the structurally related eukaryotic cAMP\u2010dependent protein kinase"],"prefix":"10.1096","volume":"31","author":[{"given":"D\u00e1maso","family":"S\u00e1nchez\u2010Carrera","sequence":"first","affiliation":[{"name":"Laboratorio de Hematolog\u00eda Molecular Servicio de Hematolog\u00eda y Hemoterapia Hospital Universitario Marqu\u00e9s de Valdecilla\u2013Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL) Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Bravo\u2010Navas","sequence":"additional","affiliation":[{"name":"Laboratorio de Hematolog\u00eda Molecular Servicio de Hematolog\u00eda y Hemoterapia Hospital Universitario Marqu\u00e9s de Valdecilla\u2013Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL) Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Cabez\u00f3n","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular and Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (IBBTEC) Universidad de Cantabria\u2013Consejo Superior de Investigaciones Cientificas (CSIC) Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Arechaga","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular and Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (IBBTEC) Universidad de Cantabria\u2013Consejo Superior de Investigaciones Cientificas (CSIC) Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matilde","family":"Cabezas","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular and Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (IBBTEC) Universidad de Cantabria\u2013Consejo Superior de Investigaciones Cientificas (CSIC) Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucrecia","family":"Y\u00e1\u00f1ez","sequence":"additional","affiliation":[{"name":"Laboratorio de Hematolog\u00eda Molecular Servicio de Hematolog\u00eda y Hemoterapia Hospital Universitario Marqu\u00e9s de Valdecilla\u2013Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL) Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Pipa\u00f3n","sequence":"additional","affiliation":[{"name":"Laboratorio de Hematolog\u00eda Molecular Servicio de Hematolog\u00eda y Hemoterapia Hospital Universitario Marqu\u00e9s de Valdecilla\u2013Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL) Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,4,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2741\/Wright"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(03)00121-9"},{"key":"e_1_2_8_4_1","first-page":"187","article-title":"Fludarabine in the treatment of chronic lymphocytic leukemia: a review","volume":"5","author":"Ricci F.","year":"2009","journal-title":"Ther. 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