Hypoxia favors chemoresistance in T-ALL through an HIF1a-mediated mTORC1 inhibition loop

Lucine Fahy, Julien Calvo, Sara Chabi, Laurent Renou, Charly Le Maout, Sandrine Poglio, Thierry Leblanc, Arnaud Petit, Andre Baruchel, Paola Ballerini, Irina Naguibneva, Rima Haddad, Marie Laure Arcangeli, Frederic Mazurier, Francoise Pflumio, Benjamin Uzan

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    21 Citations (Scopus)

    Résumé

    Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1a (HIF-1a), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1a KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1a KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1a and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.

    langue originaleAnglais
    Pages (de - à)513-526
    Nombre de pages14
    journalBlood Advances
    Volume5
    Numéro de publication2
    Les DOIs
    étatPublié - 26 janv. 2021

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