| G2/M checkpoint stringency is a key parameter in the sensitivity of AML cells to genotoxic stress. | |
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MedLine Citation:
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PMID: 18212737 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Acute myeloid leukemia (AML) cells exposed to genotoxic agents arrest their cell cycle at the G2/M checkpoint and are inherently chemoresistant. To understand the mechanism of this chemoresistance, we compared the ability of immature CD34+ versus mature CD34- AML cell lines (KG1a and U937, respectively) to recover from a DNA damage-induced cell cycle checkpoint in G2. Here, we report that KG1a cells have a more stringent G2/M checkpoint response than U937 cells. We show that in both cell types, the CDC25B phosphatase participates in the G2/M checkpoint recovery and that its expression is upregulated. Furthermore, we show that CHK1 inhibition by UCN-01 in immature KG1a cells allows checkpoint exit and induces sensitivity to genotoxic agents. Similarly, UCN-01 treatment potentializes genotoxic-induced inhibition of colony formation efficiency of primary leukemic cells from AML patients. Altogether, our results demonstrate that checkpoint stringency varies during the maturation process and indicate that targeting checkpoint mechanisms might represent an attractive therapeutic opportunity for chemoresistant immature AML cells. |
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Authors:
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C Didier; C Cavelier; M Quaranta; M-O Galcera; C Demur; G Laurent; S Manenti; B Ducommun |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-01-21 |
Journal Detail:
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Title: Oncogene Volume: 27 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2008 Jun |
Date Detail:
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Created Date: 2008-06-19 Completed Date: 2008-08-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 3811-20 Citation Subset: IM |
Affiliation:
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LBCMCP-CNRS UMR5088-IFR109 Institut d'Exploration Fonctionnelle des Génomes, University of Toulouse, Toulouse, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD
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analysis Antigens, CD34 / analysis Antineoplastic Agents / toxicity Cell Division* / drug effects Cell Line, Tumor Colony-Forming Units Assay G2 Phase* Humans Leukemia, Myeloid, Acute / genetics*, pathology* Mitosis / drug effects Nocodazole / pharmacology Staurosporine / analogs & derivatives, toxicity U937 Cells cdc25 Phosphatases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD; 0/Antigens, CD34; 0/Antineoplastic Agents; 112953-11-4/7-hydroxystaurosporine; 31430-18-9/Nocodazole; 62996-74-1/Staurosporine; EC 3.1.3.48/cdc25 Phosphatases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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