PGC-1α driven mitochondrial biogenesis in stromal cells underpins mitochondrial trafficking to leukemic blasts

Marlein, Christopher R.; Zaitseva, Lyubov; Piddock, Rachel E.; Rásó‐Barnett, Lívia; Scott, Michael A.; Ingham, Christopher; Collins, Angela; Bowles, Kristian M.; Rushworth, Stuart A.

doi:10.1038/s41375-018-0221-y

Cited by 18 publications

(16 citation statements)

References 15 publications

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“…Moreover, both molecules seem to be required for AML persistence and recurrence in vivo. Indeed, mice infused with NOX2 KD AML cell lines exhibit reduced engraftment and extended overall survival, while PGC-1α KD MSCs mice display a reduced tumor volume compared to control mice [131,134]. Overall, these data pinpoint some potential targetable antigens, but much work still has to be done.…”

Section: Signaling Via Mitochondrial Transfer In Aml Nichementioning

confidence: 99%

“…According to their model, AML cells, through NADPH oxidase-2 (NOX2) activity, locally increase oxidative stress, driving MSCs to produce new mitochondria. The fully functional mitochondria are then delivered to AML cells through TNTs without causing a metabolic imbalance of MSCs as they activate the peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, the master regulator of mitochondrial biogenesis, which keeps ROS levels under control [134].…”

Section: Signaling Via Mitochondrial Transfer In Aml Nichementioning

confidence: 99%

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Location First: Targeting Acute Myeloid Leukemia Within Its Niche

Pievani

Biondi

Tomasoni

et al. 2020

JCM

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Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. The mechanism of stromal-mediated protection of leukemic cells in the BM is complex and involves many adhesion molecules, chemokines, and cytokines. Targeting these factors may represent a valuable approach to complement existing therapies and overcome microenvironment-mediated drug resistance. Some strategies for dislodging LSCs and leukemic blasts from their protective niche have already been tested in patients and are in different phases of the process of clinical development. Other strategies, such as targeting the stromal cells remodeling processes, remain at pre-clinical stages. Development of humanized xenograft mouse models, which overcome the mismatch between human leukemia cells and the mouse BM niche, is required to generate physiologically relevant, patient-specific human niches in mice that can be used to unravel the role of human AML microenvironment and to carry out preclinical studies for the development of new targeted therapies.

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Section: Signaling Via Mitochondrial Transfer In Aml Nichementioning

confidence: 99%

Section: Signaling Via Mitochondrial Transfer In Aml Nichementioning

confidence: 99%

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

Pievani

Biondi

Tomasoni

et al. 2020

JCM

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“…Chemotherapy further increases the already high oxidative stress of the leukemic microenvironment, enhances the transfer of mitochondria from BMSC to leukemic cells, and promotes AML proliferation and relapse [146,176]. While the donation of functional mitochondria had no apparent adverse effect on the metabolic health of BMSC, AML blasts develop an increase in mitochondrial mass which is further enhanced by increased mitochondrial biogenesis in BMSC through peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which is essential for sustained mitochondrial transfer to AML cells [179]. Concomitantly, the depletion of TNT formation by cytochalasin B or inhibition of ROS by N-acetyl cysteine (NAC), glutathione, and diphenyleneiodonium (DPI) in leukemic cells shows a significant decrease in AML blasts [176].…”

Section: Mitochondria Trafficking Mediated By Connexins In Leukemiamentioning

confidence: 99%

Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance

Singh

Cancelas

2020

IJMS

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The crosstalk between hematopoietic stem cells (HSC) and bone marrow (BM) microenvironment is critical for homeostasis and hematopoietic regeneration in response to blood formation emergencies after injury, and has been associated with leukemia transformation and progression. Intercellular signals by the BM stromal cells in the form of cell-bound or secreted factors, or by physical interaction, regulate HSC localization, maintenance, and differentiation within increasingly defined BM HSC niches. Gap junctions (GJ) are comprised of arrays of membrane embedded channels formed by connexin proteins, and control crucial signaling functions, including the transfer of ions, small metabolites, and organelles to adjacent cells which affect intracellular mechanisms of signaling and autophagy. This review will discuss the role of GJ in both normal and leukemic hematopoiesis, and highlight some of the most novel approaches that may improve the efficacy of cytotoxic drugs. Connexin GJ channels exert both cell-intrinsic and cell-extrinsic effects on HSC and BM stromal cells, involved in regenerative hematopoiesis after myelosuppression, and represent an alternative system of cell communication through a combination of electrical and metabolic coupling as well as organelle transfer in the HSC niche. GJ intercellular communication (GJIC) in the HSC niche improves cellular bioenergetics, and rejuvenates damaged recipient cells. Unfortunately, they can also support leukemia proliferation and survival by creating leukemic niches that provide GJIC dependent energy sources and facilitate chemoresistance and relapse. The emergence of new strategies to disrupt self-reinforcing malignant niches and intercellular organelle exchange in leukemic niches, while at the same time conserving normal hematopoietic GJIC function, could synergize the effect of chemotherapy drugs in eradicating minimal residual disease. An improved understanding of the molecular basis of connexin regulation in normal and leukemic hematopoiesis is warranted for the re-establishment of normal hematopoiesis after chemotherapy.

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“…AML cells, through NADPH oxidase-2 (NOX2) activity, locally increase oxidative stress, pushing MSCs to increase mitochondria production (150). The extra-mitochondria are transferred to AML cells without any side effect on the metabolic health of MSCs through the activation of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, the master regulator of mitochondrial biogenesis, which is essential for AML-directed mitochondrial transfer (159). Thus, AML cells with extra-functionally active mitochondria might gain a metabolic advantage, and possibly be relevant for chemo-resistance.…”

Section: The Yang Of Mscs: Msc Role In Aml Onset and Progressionmentioning

confidence: 99%

The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia

Ciciarello

Corradi

Loscocco³

et al. 2019

Front. Oncol.

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Mesenchymal stromal cells (MSCs) have, for a long time, been recognized as pivotal contributors in the set up and maintenance of the hematopoietic stem cell (HSC) niche, as well as in the development and differentiation of the lympho-hematopoietic system. MSCs also have a unique immunomodulatory capacity, which makes them able to affect, both in vitro and in vivo, the function of immune cells. These features, namely the facilitation of stem cell engraftment and the inhibition of lymphocyte responses, have both proven essential for successful allogeneic stem cell transplantation (allo-SCT), which remains the only curative option for several hematologic malignancies. For example, in steroid-refractory acute graft-vs. host disease developing after allo-SCT, MSCs have produced significant results and are now considered a treatment option. However, more recently, the other side of the MSC coin has been unveiled, because of their emerging role in creating a protective and immune-tolerant microenvironment able to support the survival of leukemic cells and affect the response to therapies. In this light, it has been proposed that the failure of current treatments to efficiently override the stroma-mediated protection of leukemic cells accounts for the high rate of relapse in acute myeloid leukemia, at least in part. In this review, we will focus on emerging microenvironment-driven mechanisms conferring a survival advantage to leukemic cells overt physiological HSCs. This body of evidence increasingly highlights the opportunity to consider tumor-microenvironment interactions when designing new therapeutic strategies.

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PGC-1α driven mitochondrial biogenesis in stromal cells underpins mitochondrial trafficking to leukemic blasts

Cited by 18 publications

References 15 publications

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance

The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia

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