ArticleOncotarget2017
Distinct signaling events promote resistance to mitoxantrone and etoposide in pediatric AML: a Children's Oncology Group report.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed, 7 citations in OpenAlex.
- Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2021Article
- Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation.Blood advances · 2019Article
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Authors and funding
4 authors at 3 institutions in 1 country.
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Abstract
Despite aggressive chemotherapy including mitoxantrone and etoposide, relapse occurs for almost half of children with acute myeloid leukemia (AML). Since both drugs inhibit topoisomerase II and cause DNA double strand breaks, resistance could be achieved by enhanced DNA damage repair (DDR), via homologous recombination (HR) and/or non-homologous end joining (NHEJ). An important source of extrinsic chemoresistance is the bone marrow stroma. We aimed to reveal intrinsic and stroma-induced signaling pathways that contribute to chemoresistance. Sixty diagnostic pediatric AML samples were cultured on or off stromal cells, with or without chemotherapy. We measured apoptosis, DNA damage signaling, and NHEJ/HR pathway activity by FACS analysis of intracellular cleaved PARP, γH2AX, pDNA-PKcs and pATM, respectively. Mitoxantrone strongly increased γH2AX and pDNA-PKcs. Neither chemotherapy drug induced pATM. DNA-PK inhibition alleviated mitoxantrone resistance for AML cells on and off stromal cells. Regarding stroma-induced signaling pathways, ERK1/2 was most consistently activated in primary AML cells by stromal cells. ERK1/2 inactivation partially restored chemosensitivity to AML cells on stromal cells. Additionally, low stroma-induced STAT3 activity and strong stroma-induced mitoxantrone resistance were associated with inferior clinical outcome. Taken together, the NHEJ DDR and ERK1/2 pathways are potential targets for reducing intrinsic and extrinsic chemotherapy resistance in pediatric AML.
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Registered trials
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