TY - JOUR
T1 - Hypoxia favors chemoresistance in T-ALL through an HIF1a-mediated mTORC1 inhibition loop
AU - Fahy, Lucine
AU - Calvo, Julien
AU - Chabi, Sara
AU - Renou, Laurent
AU - Le Maout, Charly
AU - Poglio, Sandrine
AU - Leblanc, Thierry
AU - Petit, Arnaud
AU - Baruchel, Andre
AU - Ballerini, Paola
AU - Naguibneva, Irina
AU - Haddad, Rima
AU - Arcangeli, Marie Laure
AU - Mazurier, Frederic
AU - Pflumio, Francoise
AU - Uzan, Benjamin
N1 - Publisher Copyright:
© 2021 by The American Society of Hematology.
PY - 2021/1/26
Y1 - 2021/1/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099817437&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2020002832
DO - 10.1182/bloodadvances.2020002832
M3 - Article
C2 - 33496749
AN - SCOPUS:85099817437
SN - 2473-9529
VL - 5
SP - 513
EP - 526
JO - Blood Advances
JF - Blood Advances
IS - 2
ER -