Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop

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 1 alpha (HIF-1 alpha), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1 alpha KD also restored mTOR activation in low O-2 concentrations, and inhibiting mTOR in HIF1 alpha KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1 alpha and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.

Automated summary

Leukemic cells grow slowly in hypoxic environments and become less sensitive to antileukemic drugs, indicating that hypoxic niches can protect T-ALL from the effects of chemotherapy. Inhibiting HIF-1α and activating the mTORC1 pathway may help alleviate the drug resistance of T-ALL in hypoxic niches.