Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Forte, Dorian; García-Fernández, María; Sánchez-Aguilera, Abel; Stavropoulou, Vaia; Fielding, Claire; Martín-Pérez, Daniel; López, Juan Antonio; Costa, Ana S. H.; Tronci, Laura; Nikitopoulou, Efterpi; Barber, M.; Gallipoli, Paolo; Marando, Ludovica; Castillejo, Carlos L.F. de; Tzankov, Alexandar; Dietmann, Sabine; Cavo, Michèle; Catani, Lucia; Curti, Antonio; Vázquez, Jesús; Frezza, Christian; Huntly, Brian J. P.; Schwaller, Juerg; Méndez-Ferrer, Simón

doi:10.1016/j.cmet.2020.09.001

Cited by 128 publications

(119 citation statements)

References 104 publications

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“…However, our data has shown that AML cells in co-culture present lower levels of ROS than AML cells cultured alone, which is in agreement with recent studies in primary AML and mesenchymal stromal cell co-cultures [14, 24]. The current mechanisms to describe this phenomenon involve mitochondrial transfer and activation of glutathione-related antioxidant pathways [14, 24], although previous data on haematopoietic stem cells (HSCs) revealed that HSCs can directly transfer ROS via gap junctions to stromal cells [30]. Interestingly, our data showed that the decrease in ROS levels was counteracted by inhibiting contact using a permeable membrane.…”

Section: Discussionsupporting

confidence: 93%

“…For instance, AML cells are known to interact and modulate niche components for their own support by secreting soluble factors [2–6], via exosomes [7–9] or by establishing direct interactions, mediated by gap junctions [10] or tunnelling nanotubes [11]. These interactions with components of the niche provide AML cells with survival cues, chemoresistance and increase AML relapse [2, 4, 7, 10, 12-14]. Furthermore, it has been reported that adipocytes in the niche secrete fatty acids, which are metabolised by AML cells through β-oxidation to obtain energy, protecting AML cells from apoptosis and ROS [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…How AML cells cope with high ROS levels has been intriguing and recent reports are shedding some light on whether the microenvironment plays a role in the redox metabolism of AML cells. For instance, it was reported that Nestin+ bone marrow mesenchymal stem cells (BMSCs) support AML progression by increasing the bioenergetic capacity of AML cells and providing them with glutathione (GSH)-mediated antioxidant defence to balance the excess ROS [14]. Similarly, a recent study showed that co-culturing BMSCs with AML cells leads to a decrease in AML ROS levels due to an activation of the antioxidant enzyme GPx-3 in AML cells [24].…”

Section: Introductionmentioning

confidence: 99%

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Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

Vilaplana-Lopera¹,

Almaghrabi

Papatzikas³

et al. 2021

Preprint

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SummaryAcute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, it is unclear whether AML cells could establish beneficial metabolic interactions with stromal cells. Here, we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption. By performing transcriptome analysis and tracer-based NMR studies, we show that stromal cells present a higher rate of glycolysis, and that the secreted acetate derives from pyruvate via a reactive oxygen species (ROS)-mediated process. Our data also reveals that AML cells transfer ROS to stromal cells using gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells that could be exploited as adjuvant therapy.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

Vilaplana-Lopera¹,

Almaghrabi

Papatzikas³

et al. 2021

Preprint

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“…The group of Mendez-Ferrer et al recently published a relationship between the chemoresistance of leukemic cells to AraC and MSC-induced modifications of energy/redox metabolism. Interestingly, GPX3 was overexpressed in treated leukemic cells cocultured with MSCs [ 55 ]. Altogether these data reinforce the identification of a key role of the BM microenvironment in the control of the GPx3-ROS-p38MAPK axis in leukemia and of the oxidative metabolism of leukemic blasts.…”

Section: Discussionmentioning

confidence: 99%

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

Vignon

Debeissat

Bourgeais

et al. 2020

IJMS

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The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell–cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.

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“…Dysregulation of miRNAs have been found in multiple hematological malignancies43 .Conceivably, miRNA and miRNA exchanges may induce stable phenotypic changes in cells.Several studies have indicated BMSC can provide survival and anti-apoptotic signals to AML cells and as a result support leukemogenesis44,45 . Consistent with such evidence, we here demonstrate that syntenin-deficient BMSC are able and suffice to educate different types of AML, enhancing cell survival and recapitulating at least some of the micro-environmental effects on AML observed in vivo.…”

mentioning

confidence: 99%

A syntenin-deficient microenvironment educates AML for aggressiveness

Leblanc

Fares

Goubard

et al. 2021

Preprint

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In acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify the role of environmental syntenin in the progression of AML. By in vivo approaches in syngeneic mice, we demonstrate that a syntenin-deficient environment reprograms AML blasts to survive independently of the stroma. Up-regulation of EEF1A2 in the blasts controls this gain of cell survival. Furthermore, using ex vivo co-culture systems, we show that syntenin-deficient bone marrow stromal cells (BMSC) enhance the survival of different types of AML cells, including patient samples, and suffice to educate syngeneic AML, recapitulating micro-environmental effects observed in vivo. We establish that syntenin-deficiency causes an increase of eIF5A and autophagy-related factors in BMSC, and provide evidence that the inhibition of autophagy prevents syntenin-deficient BMSC to stimulate AML survival. Altogether, these findings indicate that host-syntenin in the BM microenvironment acts as a repressor of AML aggressiveness.Key points-A syntenin-deficient host reprograms AML blasts, enhancing total protein synthesis and cell survival pathways-Autophagy in the syntenin-deficient microenvironment is responsible for the gain of AML cell survival

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Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Cited by 128 publications

References 104 publications

Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

A syntenin-deficient microenvironment educates AML for aggressiveness

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