Mitochondria in human acute myeloid leukemia cell lines have ultrastructural alterations linked to deregulation of their respiratory profiles

Mondet, Julie; Presti, Caroline Lo; Chevalier, Simon; Bertrand, Anne; Tondeur, Sylvie; Blanchet, Sandrine; Leer, Anne Mc; Pernet‐Gallay, Karin; Mossuz, Pascal

doi:10.1016/j.exphem.2021.03.001

Cited by 13 publications

(12 citation statements)

References 26 publications

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“…This strategy could be the underlying explanation for our findings. An increased mitochondrial activity and/or quantity might aid the tumor cells to satisfy their high energy demand [34]. In addition, leukemia stem cells (LSCs), in contrast to normal hematopoietic stem cells, are highly dependent on mitochondrial activity to regulate reactive oxygen species production [35].…”

Section: Discussionmentioning

confidence: 99%

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children

et al. 2022

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Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.

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Section: Discussionmentioning

confidence: 99%

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children

et al. 2022

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“…This deficiency was related to decreased number of matrix granules, mitochondria-associated endoplasmic reticulum membrane (MAM), and mitochondrial-derived vesicle (MDV) precursors, which are implicated in the regulation of cell death pathways via mitophagy and intracellular Ca 2+ concentration changes. These cells are also thought to have increased mitochondrial respiration and defective mitophagy [243].…”

Section: Additional Sex Like Comb Protein 1 (Asxl1)mentioning

confidence: 99%

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Czegle

Gray

Wang³

et al. 2021

Life

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Hematologic malignancies are known to be associated with numerous cytogenetic and molecular genetic changes. In addition to morphology, immunophenotype, cytochemistry and clinical characteristics, these genetic alterations are typically required to diagnose myeloid, lymphoid, and plasma cell neoplasms. According to the current World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, numerous genetic changes are highlighted, often defining a distinct subtype of a disease, or providing prognostic information. This review highlights how these molecular changes can alter mitochondrial bioenergetics, cell death pathways, mitochondrial dynamics and potentially be related to mitochondrial genetic changes. A better understanding of these processes emphasizes potential novel therapies.

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“…AML lysosomes also display alterations in their sphingolipid profile [ 7 ] and could be implicated in chemoresistance [ 8 ]. Regarding leukemic mitochondria, transformation induces an increase in mass and respiration [ 9 , 10 , 11 ], a reliance on OXPHOS, higher vulnerability to oxidative stress [ 10 , 11 , 12 ], and changes in the relevant ultrastructural features [ 13 ]. Indeed, disrupting the mitochondria (i.e., by inhibiting OXPHOS) was proposed as a therapeutic strategy in AML, and clinical trials are ongoing [ 11 , 12 , 14 , 15 , 16 ], although the appropriateness of this strategy was recently challenged [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia

Carbó

Cornet-Masana

Cuesta-Casanovas

et al. 2023

Cancers

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Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+–TFEB–MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias.

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Mitochondria in human acute myeloid leukemia cell lines have ultrastructural alterations linked to deregulation of their respiratory profiles

Cited by 13 publications

References 26 publications

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia

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