| Conditional TPM3-ALK and NPM-ALK transgenic mice develop reversible ALK-positive early B-cell lymphoma/leukemia. | |
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MedLine Citation:
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PMID: 20223922 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) and TPM3-ALK (nonmuscular tropomyosin 3-anaplastic lymphoma kinase) are oncogenic tyrosine kinases implicated in the pathogenesis of human ALK-positive lymphoma. We report here the development of novel conditional mouse models for ALK-induced lymphomagenesis, with the use of the tetracycline regulatory system under the control of the EmuSRalpha enhancer/promoter. The expression of either oncogene resulted in the arrest of the differentiation of early B cells and lymphomagenesis. We also observed the development of skin keratoacanthoma lesions, probably because of aberrant ALK expression in keratinocytes. The inactivation of the ALK oncogene on doxycycline treatment was sufficient to induce sustained regression of both hematopoietic tumors and skin disease. Importantly, treatment with the specific ALK inhibitor (PF-2341066) also reversed the pathologic states, showing the value of these mouse models for the validation of ALK tyrosine kinase inhibitors. Thus, our results show (1) that NPM-ALK and TPM3-ALK oncogenes are sufficient for lymphoma/leukemia development and required for tumor maintenance, hence validating ALK as potentially effective therapeutic target; and (2) for the first time, in vivo, the equal tumorigenic potential of the NPM-ALK and TPM3-ALK oncogenic tyrosine kinases. Our models offer a new tool to investigate in vivo the molecular mechanisms associated with ALK-induced lymphoproliferative disorders. |
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Authors:
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Sylvie Giuriato; Marianne Foisseau; Emilie Dejean; Dean W Felsher; Talal Al Saati; Cécile Demur; Ashraf Ragab; Anna Kruczynski; Claudine Schiff; Georges Delsol; Fabienne Meggetto |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-11 |
Journal Detail:
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Title: Blood Volume: 115 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-21 Completed Date: 2010-06-10 Revised Date: 2011-06-08 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 4061-70 Citation Subset: AIM; IM |
Affiliation:
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Inserm, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Blotting, Western Cell Differentiation Cell Proliferation Enzyme-Linked Immunosorbent Assay Flow Cytometry Humans Immunoblotting Immunoenzyme Techniques Integrases / metabolism Leukemia, B-Cell / genetics, metabolism, pathology* Lymphoma, B-Cell / genetics, metabolism, pathology* Mice Mice, Transgenic Protein-Tyrosine Kinases / genetics*, metabolism RNA, Messenger / genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Tropomyosin / genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/RNA, Messenger; 0/TPM3 protein, human; 0/Tropomyosin; EC 2.7.1.-/p80(NPM-ALK) protein; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/anaplastic lymphoma kinase; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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