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Research Article Free access | 10.1172/JCI2366

An in vitro model for cytogenetic conversion in CML. Interferon-alpha preferentially inhibits the outgrowth of malignant stem cells preserved in long-term culture.

J J Cornelissen, R E Ploemacher, B W Wognum, A Borsboom, H C Kluin-Nelemans, A Hagemeijer, and B Löwenberg

Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands. Cornelissen@hemh.azr.nl

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Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands. Cornelissen@hemh.azr.nl

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Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands. Cornelissen@hemh.azr.nl

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Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands. Cornelissen@hemh.azr.nl

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Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands. Cornelissen@hemh.azr.nl

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Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands. Cornelissen@hemh.azr.nl

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Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands. Cornelissen@hemh.azr.nl

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Published September 1, 1998 - More info

Published in Volume 102, Issue 5 on September 1, 1998
J Clin Invest. 1998;102(5):976–983. https://doi.org/10.1172/JCI2366.
© 1998 The American Society for Clinical Investigation
Published September 1, 1998 - Version history
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Abstract

IFN-alpha has been shown to prolong survival in chronic myeloid leukemia patients, but its mechanism of action is still not understood. The human cobblestone area-forming cell (CAFC) assay allows for the measurement of the concentration of normal as well as malignant stem cells, while their progeny can be measured in parallel long-term culture (LTC) in flasks. Using CAFC and LTC assays, we have examined direct effects of IFN-alpha (500; 5,000 IU/ml) on the maintenance and outgrowth of CD34-enriched normal and malignant stem cells, obtained from six patients with an established major cytogenetic response to IFN-alpha and from four nonresponding patients. CAFC concentrations were not affected by IFN-alpha. In contrast, IFN-alpha strongly inhibited the clonogenic output in flask LTC. Nucleated cells (NC) produced in LTC were evaluated by fluorescent in situ hybridization (FISH) for the presence of the Philadelphia (Ph) translocation. After 8 wk of LTC, the percentage of Ph+ NCs produced was significantly more inhibited by IFN-alpha in responding patients than in nonresponders. Control LTC without IFN-alpha showed no significant differences of Ph+ NC production between responders and nonresponders. These findings provide the first in vitro model for cytogenetic conversion and suggest that direct antiproliferative effects of IFN-alpha account for the cytogenetic response observed clinically.

Version history
  • Version 1 (September 1, 1998): No description

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