Metabolic Reprogramming in Hematologic Malignancies: Advances and Clinical Perspectives

Wang, Xin; Yu, Zhuoya; Zhou, Xiangxiang

doi:10.1158/0008-5472.can-22-0917

Cited by 14 publications

(10 citation statements)

References 148 publications

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“…Metabolic reprogramming is a hallmark of cancer progression. It can support tumorigenesis by control of nutrient and oxygen availability, and the rewriting of metabolic processes that regulate the phenotype, function, and survival of immune cells 55 . MDSCs as key regulators of immune responses, rely on glucose, glutamine, and fatty acid oxidation to maintain metabolic fitness, critical to support their immunosuppressive functions 56 .…”

Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

Daneshmandi,

Choi,

Yan

et al. 2024

Nat Commun

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Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

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Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

Daneshmandi,

Choi,

Yan

et al. 2024

Nat Commun

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“…Metabolic reprogramming is essential for maintaining the biological functions of tumor cells and immune cells [ 7 , 50 ]. As a kind of aggressive B-cell lymphoma, DLBCL is characterized by metabolic heterogeneity that is associated with drug resistance and immune microenvironment remodeling [ 51 – 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…As a prominent hallmark of cancer, metabolic reprogramming represents the phenotypic outcome and environmental influences on the molecular function of tumor cells [ 7 ]. Reorganization of tumor metabolism is characterized by increased assumption of various nutrients, including glutamine [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis

Cai

Lü

et al. 2023

Cell Death Discov.

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Metabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of reactive oxygen species (ROS) contributed to ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.

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“…Long‐term survival remains limited with the application of the existing standard regimens combining anthracyclines with cytarabine (Ara‐C) 2 . Metabolic reprogramming and adaptation act as hallmarks of AML cells, including increased glycolysis and glutaminolysis, and studies have highlighted the roles of specific metabolic enzymes and metabolites in normal haematopoietic stem cell homeostasis and leukemogenesis 3–5 . AML cells may therefore be eliminated by identifying novel metabolic targets for screening more efficient multidrug combination therapies.…”

Section: Introductionmentioning

confidence: 99%

Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression

Wang

et al. 2023

Br J Haematol

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Summary Glutamine metabolic reprogramming in acute myeloid leukaemia (AML) cells contributes to the decreased sensitivity to antileukemic drugs. Leukaemic cells, but not their myeloid counterparts, largely depend on glutamine. Glutamate dehydrogenase 1 (GDH1) is a regulation enzyme in glutaminolysis. However, its role in AML remains unknown. Here, we reported that GDH1 was highly expressed in AML: high GDH1 was one of the independent negative prognostic factors in AML cohort. The dependence of leukaemic cells on GDH1 was proved both in vitro and in vivo. High GDH1 promoted cell proliferation and reduced survival time of leukaemic mice. Targeting GDH1 eliminated the blast cells and delayed AML progression. Mechanistically, GDH1 knockdown inhibited glutamine uptake by downregulating SLC1A5. Moreover, GDH1 invalidation also inhibited SLC3A2 and abrogated the cystine‐glutamate antiporter system Xc−. The reduced cystine and glutamine disrupted the synthesis of glutathione (GSH) and led to the dysfunction of glutathione peroxidase‐4 (GPX4), which maintains the lipid peroxidation homeostasis by using GSH as a co‐factor. Collectively, triggering ferroptosis in AML cells in a GSH depletion manner, GDH1 inhibition was synthetically lethal with the chemotherapy drug cytarabine. Ferroptosis induced by inhibiting GDH1 provides an actionable therapeutic opportunity and a unique target for synthetic lethality to facilitate the elimination of malignant AML cells.

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Metabolic Reprogramming in Hematologic Malignancies: Advances and Clinical Perspectives

Cited by 14 publications

References 148 publications

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis

Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression

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