ArticleBlood advances2021
Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop.
Article in Blood advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 31 citations in OpenAlex.
- Review
- mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow.Blood advances · 2025Article
- AutoML identification of microRNA biomarkers in high-risk pediatric acute lymphoblastic leukemia.Non-coding RNA research · 2025Article
- The mitochondria as an emerging target of self-renewal in T-cell acute lymphoblastic leukemia.Cancer biology & therapy · 2025Review
- Article
- Metabolic Adaptations and Therapies in Cardiac Hypoxia: Mechanisms and Clinical Implications/ Potential Strategies.JACC. Basic to translational science · 2025Review
- High CD44 expression and enhanced E-selectin binding identified as biomarkers of chemoresistant leukemic cells in human T-ALL.Leukemia · 2025Article
- Inhibition of CRM1 reverses hypoxia-driven chemoresistance in acute myeloid leukemia via overcoming HIF-1α-mediated lysosomal sequestration.Frontiers in immunology · 2025Article
- Targeting hypoxia-inducible factor 1α in chronic graft-versus-host disease to enhance graft-versus-leukemia responses: implications for nanotherapeutics.Frontiers in immunology · 2025Review
- Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL).Experimental & molecular medicine · 2024Review
- Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in nasopharyngeal carcinoma by stabilizing H2A.Cancer cell international · 2024Article
- Leukemic Stem Cells and Hematological Malignancies.International journal of molecular sciences · 2024Review
- Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia.Asian Pacific journal of cancer prevention : APJCP · 2024Review
- HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies.Genes & diseases · 2024Review
- JUN mediates glucocorticoid resistance by stabilizing HIF1a in T cell acute lymphoblastic leukemia.iScience · 2023Article
- Integrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia.Nature communications · 2023Article
- Endothelial cell-leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities.Blood · 2023Article
- Expression of Long Non-Coding RNA H19 in Acute Lymphoblastic Leukemia.Cell journal · 2023Article
- mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters.Nature communications · 2022Article
- Hypoxic stress and hypoxia-inducible factors in leukemias.Frontiers in oncology · 2022Review
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.
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