ArticleOncogene2017
Therapeutic targeting of necroptosis by Smac mimetic bypasses apoptosis resistance in acute myeloid leukemia cells.
Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 65 citations in OpenAlex.
- BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.Leukemia · 2026Article
- Mebendazole induces ZBP-1 mediated PANoptosis of acute myeloid leukemia cells by targeting TUBA1A and exerts antileukemia effect.Journal of advanced research · 2025Article
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- Dual roles of inflammatory programmed cell death in cancer: insights into pyroptosis and necroptosis.Frontiers in pharmacology · 2024Review
- Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity.Journal of clinical medicine · 2023Article
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- The Interplay Between Autophagy and Regulated Necrosis.Antioxidants & redox signaling · 2023Review
- X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.EMBO molecular medicine · 2023Article
- Targeting regulated cell death pathways in acute myeloid leukemia.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review.International journal of molecular sciences · 2022Review
- Review
- Pan-cancer analysis of necroptosis-related gene signature for the identification of prognosis and immune significance.Discover oncology · 2022Article
- Connexin32 activates necroptosis through Src-mediated inhibition of caspase 8 in hepatocellular carcinoma.Cancer science · 2021Article
- Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines.Neoplasia (New York, N.Y.) · 2021Article
- Cell death in head and neck cancer pathogenesis and treatment.Cell death & disease · 2021Review
- Somatic Epigenetic Silencing ofClinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- The role of NF-κB and Smac/DIABLO proteins in the treatment response and survival of acute myeloid leukemia patients.Archives of medical science : AMS · 2021Article
- Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex.Cell death and differentiation · 2020Article
- Identification of MYC as an antinecroptotic protein that stifles RIPK1-RIPK3 complex formation.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
Corrections and comments
- Erratum issued
Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Resistance to apoptosis, for example due to overexpression of Inhibitor of Apoptosis (IAP) proteins, is associated with poor prognosis in acute myeloid leukemia (AML). Here, we identify that Smac mimetics such as BV6, which antagonizes IAP proteins, elicit necroptosis in AML cells, in which apoptosis is inhibited pharmacologically by caspase inhibitors or genetically by caspase-8 knockdown. Importantly, BV6 triggers necroptosis also in apoptosis-resistant patient-derived AML blasts, underlining the clinical relevance of our findings. Mechanistically, we show that BV6-induced cell death depends on key components of necroptosis signaling such as RIP1, RIP3 and MLKL, since pharmacological or genetic inhibition of these proteins significantly protects AML cells from BV6-mediated cell death, whereas PGAM5 is dispensable. Interestingly, we identify constitutive tumor necrosis factor-alpha (TNFα) secretion and an autocrine/paracrine TNFα loop as critical mediators of BV6-induced necroptosis in AML cell lines and patient-derived blasts, as the TNFα-blocking antibody Enbrel or tumor necrosis factor-alpha receptor 1 (TNFR1) knockdown significantly rescue cell death. Notably, AML cells exhibit high basal levels of TNFα compared to non-malignant CD34+ cells, which is further increased by BV6. In conclusion, this is the first report showing that Smac mimetics circumvent apoptosis resistance in AML cells by inducing necroptosis in a TNFα-dependent manner, which has important implications for the development of new strategies to overcome treatment resistance in AML.
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