Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage

Niu, Li-Ting; Wang, Yuqing; Wong, Catherine C. L.; Gao, Shuaixin; Mo, Xiao‐Dong; Huang, Xiao‐Jun

doi:10.1016/j.tranon.2021.101159

Cited by 5 publications

(7 citation statements)

References 56 publications

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“…Another study showed that g-interferon-inducible lysosomal thiol reductase (GILT) inhibition enhances AML chemosensitivity by elevating reactive oxygen species (ROS) levels and inducing oxidative mitochondrial-damage-mediated apoptosis. Similarly, inhibition of the PI3K/Akt/NRF2 antioxidant pathway enhanced the intracellular oxidative state and increased the chemosensitivity of AML [ 175 ].…”

Section: Targeting Lysosomes In Amlmentioning

confidence: 99%

RETRACTED: Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia

Jain

Bose

Arya

et al. 2022

Cancers

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Lysosomes are cellular organelles that regulate essential biological processes such as cellular homeostasis, development, and aging. They are primarily connected to the degradation/recycling of cellular macromolecules and participate in cellular trafficking, nutritional signaling, energy metabolism, and immune regulation. Therefore, lysosomes connect cellular metabolism and signaling pathways. Lysosome’s involvement in the critical biological processes has rekindled clinical interest towards this organelle for treating various diseases, including cancer. Recent research advancements have demonstrated that lysosomes also regulate the maintenance and hemostasis of hematopoietic stem cells (HSCs), which play a critical role in the progression of acute myeloid leukemia (AML) and other types of cancer. Lysosomes regulate both HSCs’ metabolic networks and identity transition. AML is a lethal type of blood cancer with a poor prognosis that is particularly associated with aging. Although the genetic landscape of AML has been extensively described, only a few targeted therapies have been produced, warranting the need for further research. This review summarizes the functions and importance of targeting lysosomes in AML, while highlighting the significance of lysosomes in HSCs maintenance.

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Section: Targeting Lysosomes In Amlmentioning

confidence: 99%

RETRACTED: Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia

Jain

Bose

Arya

et al. 2022

Cancers

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“…progenitor cells. 25 These data suggest that IFN-γ-induced GILT could be one of the factors accounting for chemoresistance in AML and explain why chemoresistant HSC-like cells are overexposed or are more responsive to IFN-γ. In addition to IFN-γ-induced GILT, our results showed that HSC-like cells in the non-CR group had upregulated MHC II antigen processing and presenting activity.…”

Section: Discussionmentioning

confidence: 83%

“…Persistent exposure to IFN‐γ contributes to the loss of HSCs by disrupting HSC quiescence and facilitating excessive terminal differentiation 23 . Furthermore, IFN‐γ induces GILT reductase expression, 24 and the GILT gene is upregulated in chemoresistant CD34+ progenitor cells 25 . These data suggest that IFN‐γ‐induced GILT could be one of the factors accounting for chemoresistance in AML and explain why chemoresistant HSC‐like cells are overexposed or are more responsive to IFN‐γ.…”

Section: Discussionmentioning

confidence: 95%

Chemoresistance in acute myeloid leukemia: An alternative single‐cell RNA sequencing approach

Cheng

Hsiao

Chen

et al. 2023

Hematological Oncology

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Our previous study demonstrated that myc, mitochondrial oxidative phosphorylation, mTOR, and stemness are independently responsible for chemoresistance in acute myeloid leukemia (AML) cells. This study aimed to identify potential mechanisms of chemoresistance of the “7 + 3” induction in AML by using a single‐cell RNA sequencing (scRNA‐seq) approach. In the present study, 13 untreated patients with de novo AML were enrolled and stratified into two groups: complete remission (CR; n = 8) and non‐CR (n = 5). Single‐cell RNA sequencing was used to analyze genetic profiles of 28,950 AML cells from these patients; results were validated using a previously published bulk RNA‐seq dataset. Our study results showed chemoresistant AML cells had premature accumulation during early hematopoiesis. Hematopoietic stem cell‐like cells from the non‐CR group expressed more leukemic stem cell markers (CD9, CD82, IL3RA, and IL1RAP) than those from the CR group. Chemoresistant progenitor cells had impaired myeloid differentiation owing to early arrest of hematopoiesis. Notably, AML cells analyzed by scRNA‐seq and bulk RNA‐seq harbored a comparable myeloid lineage cell fraction, which internally validated our results. Using the TCGA database, our analysis demonstrated that patients with AML with higher expression of chemoresistant genetic markers (IL3RA and IL1RAP) had a worse overall survival (p < 0.01 for IL3RA; p < 0.05 for IL1RAP). In conclusion, AML cells responsive and resistant to the “7 + 3” induction were derived from a diverse cancerous hematopoietic stem cell population, as indicated by the specific genetic biomarkers obtained using scRNA‐seq approach. Furthermore, arrest of hematopoiesis was shown to occur earlier in chemoresistant AML cells, furthering the current understanding of chemoresistance in AML.

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“…BM samples were acquired before the first induction chemotherapy. Cell sorting and mass spectrometry measurements were followed as published study ( 8 ). The diagnosis, classifications, and risk stratification were based on European Leukemia Net (ELN) recommendations ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

“…Enoyl-CoA hydratase domain containing 3 (ECHDC3), broadly expressed in adipocytes, is predicted to be active in the mitochondrion, involving fatty acid biosynthesis and lipid metabolism ( 7 ). Our team firstly reported that ECHDC3 was upregulated in CD34 + progenitors of chemoresistant AML ( 8 ), whereas the prognostic significance and function of ECHDC3 in AML have yet to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification

Zhao

Niu²,

Hu³

et al. 2022

Front. Oncol.

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BackgroundEnoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34+ progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified.MethodsIn the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People’s Hospital and tested for ECHDC3 in enriched CD34+ cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature.ResultsBy Kaplan-Meier analysis, patients with ECHDC3high demonstrated inferior overall survival (OS) compared to those with ECHDC3low both in the training (2-year OS, 55.6% vs. 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% vs. 24.3%, p = 0.002). In addition, ECHDC3high predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% vs. 26.3%, p = 0.039) or FLT3+NPM1− adverse (adv) risk (4-year OS, 6.4% vs. 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013–1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% vs. 23.5%, p < 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin.ConclusionThese bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.

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Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage

Cited by 5 publications

References 56 publications

RETRACTED: Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia

RETRACTED: Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia

Chemoresistance in acute myeloid leukemia: An alternative single‐cell RNA sequencing approach

Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification

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