Inhibition of Oxidative Phosphorylation Reverses Bone Marrow Hypoxia Visualized in Imageable Syngeneic B-ALL Mouse Model

Rytelewski, Mateusz; Harutyunyan, Karine G.; Baran, Natalia; Mallampati, Saradhi; Zal, Malgorzata Anna; Cavazos, Antonio; Butler, Jason M.; Konoplev, Sergej; Khatib, Mirna El; Plunkett, Shane; Marszalek, Joseph R.; Andreeff, Michael; Żal, Tomasz; Konopleva, Marina

doi:10.3389/fonc.2020.00991

Cited by 11 publications

(7 citation statements)

References 67 publications

(86 reference statements)

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“…Recent studies showed that CD39 expression was not induced by IFN-γ [ 59 , 60 ] whereas it can be induced under hypoxic conditions [ 61 , 62 ]. ETCI inhibitors have already been reported to interfere with HIF stabilization such as IACS [ 15 , 63 ] and metformin [ 64 , 65 , 66 ]. EVT-701 was also developed from a screening campaign to characterize HIF-1α inhibitors [ 22 ]; therefore, we propose an impairment of hypoxic signaling by interfering with HIF-1α stabilization as the mechanism by which EVT-701 decreases CD39 expression.…”

Section: Discussionmentioning

confidence: 99%

Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

Luna-Yolba

Marmoiton²,

Gigo³

et al. 2021

Cancers

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Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the anti-tumor response. The modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve the therapy outcome for AML patients. However, the effect of mitochondrial inhibitors on the immune compartment in the context of AML is yet to be explored. Immune checkpoints such as ectonucleotidase CD39 and programmed dead ligand 1 (PD-L1) have been reported to be expressed in AML and linked to chemo-resistance and a poor prognosis. In the present study, we first demonstrated that a novel selective electron transfer chain complex (ETC) I inhibitor, EVT-701, decreased the OxPHOS metabolism of murine and human cytarabine (AraC)-resistant leukemic cell lines. Furthermore, we showed that while AraC induced an immune response regulation by increasing CD39 expression and by reinforcing the interferon-γ/PD-L1 axis, EVT-701 reduced CD39 and PD-L1 expression in vitro in a panel of both murine and human AML cell lines, especially upon AraC treatment. Altogether, this work uncovers a non-canonical function of ETCI in controlling CD39 and PD-L1 immune checkpoints, thereby improving the anti-tumor response in AML.

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Section: Discussionmentioning

confidence: 99%

Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

Luna-Yolba

Marmoiton²,

Gigo³

et al. 2021

Cancers

View full text Add to dashboard Cite

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“…Amongst others, alterations in IKZF1, TP53-, CDKN2A, CREBBP, NR3C2, MSH6, PRPS1, PRPS2, NT5C2 are ETV6 are associated with unfavorable outcome and/or therapy resistance in B-ALL [400][401][402][403]. Regarding mitochondrial biogenesis in B-ALL, a recent pre-clinical data showed high oxygen consumption, which can be a future therapeutic target in therapy-resistant B-ALL [404].…”

Section: Acute Lymphoblastic Leukemia (All)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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“…Vascular remodeling is a feature of leukemia progression. It has been shown in a murine model of BCR-ABL1 B-ALL that during leukemia progression, there is an increase in blood vessel density and therefore a higher oxygen supply ( 80 ). However, because of high O 2 consumption by leukemic blasts and despite an important extracellular O 2 supply, intracellular hypoxia is elevated.…”

Section: Leukemic B Cell Nichesmentioning

confidence: 99%

Toward Therapeutic Targeting of Bone Marrow Leukemic Niche Protective Signals in B-Cell Acute Lymphoblastic Leukemia

et al. 2021

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B-cell acute lymphoblastic leukemia (B-ALL) represents the malignant counterpart of bone marrow (BM) differentiating B cells and occurs most frequently in children. While new combinations of chemotherapeutic agents have dramatically improved the prognosis for young patients, disease outcome remains poor after relapse or in adult patients. This is likely due to heterogeneity of B-ALL response to treatment which relies not only on intrinsic properties of leukemic cells, but also on extrinsic protective cues transmitted by the tumor cell microenvironment. Alternatively, leukemic cells have the capacity to shape their microenvironment towards their needs. Most knowledge on the role of protective niches has emerged from the identification of mesenchymal and endothelial cells controlling hematopoietic stem cell self-renewal or B cell differentiation. In this review, we discuss the current knowledge about B-ALL protective niches and the development of therapies targeting the crosstalk between leukemic cells and their microenvironment.

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Inhibition of Oxidative Phosphorylation Reverses Bone Marrow Hypoxia Visualized in Imageable Syngeneic B-ALL Mouse Model

Cited by 11 publications

References 67 publications

Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Toward Therapeutic Targeting of Bone Marrow Leukemic Niche Protective Signals in B-Cell Acute Lymphoblastic Leukemia

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