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Article: Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice

TitleMutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice
Authors
Issue Date2011
Citation
Nature Genetics, 2011, v. 43, n. 5, p. 470-476 How to Cite?
AbstractAcute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis whose largest subgroup is characterized by somatic mutations in NPM1, which encodes nucleophosmin. These mutations, termed NPM1c, result in cytoplasmic dislocation of nucleophosmin and are associated with distinctive transcriptional signatures, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells causes Hox gene overexpression, enhanced self renewal and expanded myelopoiesis. One third of mice developed delayed-onset AML, suggesting a requirement for cooperating mutations. We identified such mutations using a Sleeping Beauty transposon, which caused rapid-onset AML in 80% of mice with Npm1c, associated with mutually exclusive integrations in Csf2, Flt3 or Rasgrp1 in 55 of 70 leukemias. We also identified recurrent integrations in known and newly discovered leukemia genes including Nf1, Bach2, Dleu2 and Nup98. Our results provide new pathogenetic insights and identify possible therapeutic targets in NPM1c+ AML. © 2011 Nature America, Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/249049
ISSN
2017 Impact Factor: 27.125
2015 SCImago Journal Rankings: 23.762
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorVassiliou, George S.-
dc.contributor.authorCooper, Jonathan L.-
dc.contributor.authorRad, Roland-
dc.contributor.authorLi, Juan-
dc.contributor.authorRice, Stephen-
dc.contributor.authorUren, Anthony-
dc.contributor.authorRad, Lena-
dc.contributor.authorEllis, Peter-
dc.contributor.authorAndrews, Rob-
dc.contributor.authorBanerjee, Ruby-
dc.contributor.authorGrove, Carolyn-
dc.contributor.authorWang, Wei-
dc.contributor.authorLiu, Pentao-
dc.contributor.authorWright, Penny-
dc.contributor.authorArends, Mark-
dc.contributor.authorBradley, Allan-
dc.date.accessioned2017-10-27T05:58:58Z-
dc.date.available2017-10-27T05:58:58Z-
dc.date.issued2011-
dc.identifier.citationNature Genetics, 2011, v. 43, n. 5, p. 470-476-
dc.identifier.issn1061-4036-
dc.identifier.urihttp://hdl.handle.net/10722/249049-
dc.description.abstractAcute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis whose largest subgroup is characterized by somatic mutations in NPM1, which encodes nucleophosmin. These mutations, termed NPM1c, result in cytoplasmic dislocation of nucleophosmin and are associated with distinctive transcriptional signatures, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells causes Hox gene overexpression, enhanced self renewal and expanded myelopoiesis. One third of mice developed delayed-onset AML, suggesting a requirement for cooperating mutations. We identified such mutations using a Sleeping Beauty transposon, which caused rapid-onset AML in 80% of mice with Npm1c, associated with mutually exclusive integrations in Csf2, Flt3 or Rasgrp1 in 55 of 70 leukemias. We also identified recurrent integrations in known and newly discovered leukemia genes including Nf1, Bach2, Dleu2 and Nup98. Our results provide new pathogenetic insights and identify possible therapeutic targets in NPM1c+ AML. © 2011 Nature America, Inc. All rights reserved.-
dc.languageeng-
dc.relation.ispartofNature Genetics-
dc.titleMutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice-
dc.typeArticle-
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1038/ng.796-
dc.identifier.pmid21441929-
dc.identifier.scopuseid_2-s2.0-79955469651-
dc.identifier.volume43-
dc.identifier.issue5-
dc.identifier.spage470-
dc.identifier.epage476-
dc.identifier.eissn1546-1718-
dc.identifier.isiWOS:000289972600019-

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