dc.contributor.author | Morgado-Palacin, Isabel | |
dc.contributor.author | Day, Amanda | |
dc.contributor.author | Murga, Matilde | |
dc.contributor.author | Lafarga, Vanesa | |
dc.contributor.author | Anton, Marta Elena | |
dc.contributor.author | Tubbs, Anthony | |
dc.contributor.author | Chen, Hua Tang | |
dc.contributor.author | Ergan, Aysegul | |
dc.contributor.author | Anderson, Rhonda | |
dc.contributor.author | Bhandoola, Avinash | |
dc.contributor.author | Pike, Kurt G | |
dc.contributor.author | Barlaam, Bernard | |
dc.contributor.author | Cadogan, Elaine | |
dc.contributor.author | Wang, Xi | |
dc.contributor.author | Pierce, Andrew J | |
dc.contributor.author | Hubbard, Chad | |
dc.contributor.author | Armstrong, Scott A | |
dc.contributor.author | Nussenzweig, André | |
dc.contributor.author | Fernandez-Capetillo, Oscar | |
dc.date.accessioned | 2024-02-09T11:25:30Z | |
dc.date.available | 2024-02-09T11:25:30Z | |
dc.date.issued | 2016-09-13 | |
dc.identifier.citation | Sci Signal . 2016;9(445):ra91. d | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/17690 | |
dc.description.abstract | Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias. | es_ES |
dc.description.sponsorship | Work in O.F.-C. laboratory was supported by Fundacion Botin, by Banco Santander through its Santander Universities Global Division, and by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2014-57791-REDC and SVP-2013-068072), Fundacio La Marato de TV3, the Howard Hughes Medical Institute, and the European Research Council (ERC-617840). The A.N. laboratory was supported by the Intramural Research Program of the NIH, the National Cancer Institute (NCI), the Center for Cancer Research, an Ellison Medical Foundation Senior Scholar in Aging, and the Alex Lemonade Stand Foundation Award. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | American Association for the Advancement of Science (AAAS) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject.mesh | Ataxia Telangiectasia Mutated Proteins | es_ES |
dc.subject.mesh | Gene Rearrangement | es_ES |
dc.subject.mesh | Histone-Lysine N-Methyltransferase | es_ES |
dc.subject.mesh | Leukemia, Myeloid, Acute | es_ES |
dc.subject.mesh | Myeloid-Lymphoid Leukemia Protein | es_ES |
dc.subject.mesh | Neoplasms, Experimental | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Xenograft Model Antitumor Assays | es_ES |
dc.title | Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 27625305 | es_ES |
dc.format.volume | 9 | es_ES |
dc.format.number | 445 | es_ES |
dc.format.page | ra91 | es_ES |
dc.identifier.doi | 10.1126/scisignal.aad8243 | es_ES |
dc.contributor.funder | Fundación La Marató TV3 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Howard Hughes Medical Institute | es_ES |
dc.contributor.funder | United States Department of Health and Human Services | es_ES |
dc.contributor.funder | Lawrence Ellison Foundation | es_ES |
dc.contributor.funder | Banco Santander | es_ES |
dc.contributor.funder | Botín Foundation | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1937-9145 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1126/scisignal.aad8243. | es_ES |
dc.identifier.journal | Science signaling | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Inestabilidad Genómica | es_ES |
dc.identifier.pmc | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066844/ | |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/617840/EU | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFIS | info:eu-repo/grantAgreement/ES/SAF2014-57791-REDC | es_ES |
dc.relation.projectFIS | info:eu-repo/grantAgreement/SVP-2013-068072 | es_ES |