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Frequency and dynamics of leukemia-initiating cells during short-term ex vivo culture informs outcomes in acute myeloid leukemia patients

Griessinger, Emmanuel, Anjos-Afonso, Fernando, Vargaftig, Jacques, Taussig, David C., Lassailly, Francois, Prebet, Thomas, Imbert, Veronique, Nebout, Marielle, Vey, Norbert, Chabannon, Christian, Filby, Andrew, Bollet-Quivogne, Frederic, Gribben, John G., Peyron, Jean-Francois and Bonnet, Dominique 2016. Frequency and dynamics of leukemia-initiating cells during short-term ex vivo culture informs outcomes in acute myeloid leukemia patients. Cancer Research 76 (8) , pp. 2082-2086. 10.1158/0008-5472.CAN-15-2063

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Acute myeloid leukemia (AML) is sustained by a subpopulation of rare leukemia-initiating cells (LICs), detectable by their capacity to self-renew and generate non-LICs in vivo. The xenograft assay captures functional properties of LICs that have clinical prognostic value, but the long duration of xenotransplantation has hampered its implementation in the clinic. Here, we describe an ex vivo co-culture system in which the frequency of leukemic long-term culture-initiating cells (L-LTC-ICs) can be used as a reliable read-out of LIC activity over one week. We analyzed 92 AML patients classified as having a poor, intermediate, or favorable prognosis at time of diagnosis. Ex vivo limiting dilution analyses demonstrated that the frequency of L-LTC-ICs was 5-7 times higher in intermediate and poor prognosis samples compared with favorable samples after five weeks of co-culture with MS-5 stromal cells. To simplify and shorten this test, we defined a fluorescence dilution factor (FDF) as the ratio of the median fluorescence intensity, based on CFSE staining, before and after one week of co-culture. L-LTC-IC proliferation, monitored over one week, was strongly correlated to L-LTC-IC frequency. A higher FDF was evident in poor prognosis AMLs or in samples capable of engrafting NSG mice compared with favorable prognosis AMLs or non-engrafters. Notably, the FDF could classify intermediate prognosis patients with normal karyotype into two groups differing in overall survival. This non-genetic and non-in vivo approach represents a new clinically relevant tool for rapidly and reliably predicting AML patient outcome.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Date of Acceptance: 3 January 2016
Last Modified: 07 Jan 2021 15:10

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