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Article: Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARα and NPM-RARα
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TitleDistinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARα and NPM-RARα
 
AuthorsCheng, GX7 2 1
Zhu, XH6
Men, XQ6
Wang, L6
Huang, QH6
Jin, XL6
Xiong, SM6
Zhu, J6
Guo, WM6
Chen, JQ2
Xu, SF2
So, E5
Chan, LC5
Waxman, S4
Zelent, A3
Chen, GQ6
Dong, S6
Liu, JX6
Chen, SJ6 7
 
Issue Date1999
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationProceedings Of The National Academy Of Sciences Of The United States Of America, 1999, v. 96 n. 11, p. 6318-6323 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.96.11.6318
 
AbstractAcute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARα and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RARα and NPM- RARα. PLZF-RARα transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM-RARα transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RARα transgenic mice, those from NPM-RARα transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0.01 μM, 0.1 μM, and 1.0 μM for RARα-RXRα, NPM-RARα, and PML-RARα, respectively, but not observed for PLZF-RARα even in the presence of 10 μM ATRA. We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expressing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RARα and NPM-RARα and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
 
ISSN0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
DOIhttp://dx.doi.org/10.1073/pnas.96.11.6318
 
PubMed Central IDPMC26879
 
ISI Accession Number IDWOS:000080527100074
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorCheng, GX
 
dc.contributor.authorZhu, XH
 
dc.contributor.authorMen, XQ
 
dc.contributor.authorWang, L
 
dc.contributor.authorHuang, QH
 
dc.contributor.authorJin, XL
 
dc.contributor.authorXiong, SM
 
dc.contributor.authorZhu, J
 
dc.contributor.authorGuo, WM
 
dc.contributor.authorChen, JQ
 
dc.contributor.authorXu, SF
 
dc.contributor.authorSo, E
 
dc.contributor.authorChan, LC
 
dc.contributor.authorWaxman, S
 
dc.contributor.authorZelent, A
 
dc.contributor.authorChen, GQ
 
dc.contributor.authorDong, S
 
dc.contributor.authorLiu, JX
 
dc.contributor.authorChen, SJ
 
dc.date.accessioned2008-06-12T06:42:00Z
 
dc.date.available2008-06-12T06:42:00Z
 
dc.date.issued1999
 
dc.description.abstractAcute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARα and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RARα and NPM- RARα. PLZF-RARα transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM-RARα transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RARα transgenic mice, those from NPM-RARα transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0.01 μM, 0.1 μM, and 1.0 μM for RARα-RXRα, NPM-RARα, and PML-RARα, respectively, but not observed for PLZF-RARα even in the presence of 10 μM ATRA. We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expressing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RARα and NPM-RARα and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
 
dc.description.naturepublished_or_final_version
 
dc.format.extent384 bytes
 
dc.format.mimetypetext/html
 
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 1999, v. 96 n. 11, p. 6318-6323 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.96.11.6318
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.96.11.6318
 
dc.identifier.epage6323
 
dc.identifier.isiWOS:000080527100074
 
dc.identifier.issn0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
dc.identifier.issue11
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC26879
 
dc.identifier.pmid10339585
 
dc.identifier.scopuseid_2-s2.0-13044268455
 
dc.identifier.spage6318
 
dc.identifier.urihttp://hdl.handle.net/10722/49415
 
dc.identifier.volume96
 
dc.languageeng
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
 
dc.relation.referencesReferences in Scopus
 
dc.rightsNational Academy of Sciences Proceedings. Copyright © National Academy of Sciences.
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshDNA-Binding Proteins - genetics
 
dc.subject.meshLeukemia, Promyelocytic, Acute - genetics - pathology - physiopathology
 
dc.subject.meshOncogene Proteins, Fusion - genetics
 
dc.subject.meshReceptors, Retinoic Acid - genetics
 
dc.subject.meshTranscription Factors - genetics
 
dc.titleDistinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARα and NPM-RARα
 
dc.typeArticle
 
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Author Affiliations
  1. Shanghai Liver Disease Research Center
  2. Yangzhou University
  3. Institute of Cancer Research London
  4. The Mount Sinai Medical Center
  5. The University of Hong Kong
  6. Shanghai Second Medical University
  7. Ruijin Hospital