The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage

Jun, Sojeong; Mahesula, Swetha; Mathews, Thomas P.; Martin-Sandoval, Misty S.; Zhao, Zhiyu; Piskounova, Elena; Agathocleous, Michalis

doi:10.1016/j.cmet.2021.07.016

Cited by 46 publications

(51 citation statements)

References 91 publications

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“…This is consistent with the requirement of MPC1 for  T cell development (Ramstead et al, 2020). Similarly, pyruvate dehydrogenase is also required for T cell development (Jun et al, 2021). B cells were not affected by the loss of Mpc2 at any timepoint (Figure 3).…”

Section: Mature Myeloid Cells Diminish Then Rapidly Recover After Mpc2 Deletionsupporting

confidence: 85%

Progenitor-intrinsic Metabolic Sensing Promotes Hematopoietic Homeostasis

Pizzato

Wang

Wolfgang

et al. 2021

Preprint

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Hematopoietic homeostasis is maintained by stem and progenitor cells in part by extrinsic feedback cues triggered by mature cell loss. We demonstrate a different mechanism by which hematopoietic progenitors intrinsically anticipate and prevent the loss of mature progeny through metabolic switches. We examined hematopoiesis in mice conditionally deficient in long-chain fatty acid oxidation (carnitine palmitoyltransferase 2, Cpt2), glutaminolysis (glutaminase, Gls), or mitochondrial pyruvate import (mitochondrial pyruvate carrier 2, Mpc2). While genetic ablation of Cpt2 or Gls minimally impacted most blood lineages, deletion of Mpc2 led to a sharp decline in mature myeloid cells. However, MPC2-deficient myeloid cells rapidly recovered due to a transient increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was intrinsic to MPC2-deficient progenitors and accompanied by a metabolic switch to glutaminolysis. Thus, hematopoietic progenitors intrinsically adjust to metabolic perturbations independently of feedback from downstream mature cells to maintain homeostasis.

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Section: Mature Myeloid Cells Diminish Then Rapidly Recover After Mpc2 Deletionsupporting

confidence: 85%

Progenitor-intrinsic Metabolic Sensing Promotes Hematopoietic Homeostasis

Pizzato

Wang

Wolfgang

et al. 2021

Preprint

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“…1E). Together, these data illustrated that circulating lymphocyte precursors and stem cells in the thymus and bone marrow also undergo selection against the mutation, in addition to what might be induced in peripheral immune cells, in agreement with studies showing increased oxidative metabolism in proliferating hematopoietic stem cells (HSCs) 48 , and bursts of high glucose uptake in the common lymphoid progenitor and thymocytes 49 .…”

Section: Resultssupporting

confidence: 86%

Antigen receptor stimulation drives selection against pathogenic mtDNA variants that dysregulate lymphocyte responses

Zhang

Koolmeister

Han

et al. 2021

Preprint

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Pathogenic mitochondrial (mt)DNA molecules can exhibit heteroplasmy in single cells and tissues and cause a range of clinical phenotypes, although their contribution to immunity is poorly understood. Here, in mice carrying heteroplasmic C5024T in mt-tRNA Ala – that impairs oxidative phosphorylation – we found a reduced mutation burden in peripheral T and B memory lymphocyte subsets, compared to their naive counterparts. Furthermore, selection diluting the mutation was induced in vitro by triggering T and B cell antigen receptors. While C5024T dysregulated naive CD8+ T cell respiration and metabolic remodeling post-activation, these phenotypes were partially ameliorated by selection. Analogous to mice, peripheral blood memory T and B lymphocyte subsets from human MELAS (Mitochondrial Encephelomyopathy with Lactic Acidoses and Stroke-like episodes) patients – carrying heteroplasmic A3243G in mt-tRNA Leu – displayed a reduced mutation burden, compared to naive cells. In both humans and mice, mtDNA selection was observed in IgG+ antigen-specific B cells after SARS-CoV-2 Spike vaccination, illustrating an ongoing process in vivo. Taken together, these data illustrate purifying selection of pathogenic mtDNA variants during the oxidative phosphorylation checkpoints of the naive-memory lymphocyte transition.

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“…Nevertheless, the glucose uptake rate is lower in HSCs than progenitors or more differentiated hematopoietic cells in the bone marrow. 22 Liang et al showed that repression of lysosomal degradation by pharmacological V-ATPase inhibition promoted HSCs’ quiescence, which is associated with less glucose uptake. This led to improve ex vivo maintenance of functional HSCs and enhance their competitive repopulation ability upon transplantation.…”

Section: Anaerobic Glycolysis Is Critical To Preserve Hsc Quiescencementioning

confidence: 99%

Metabolic Regulation of Hematopoietic Stem Cells

2022

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Cellular metabolism is a key regulator of hematopoietic stem cell (HSC) maintenance. HSCs rely on anaerobic glycolysis for energy production to minimize the production of reactive oxygen species and shift toward mitochondrial oxidative phosphorylation upon differentiation. However, increasing evidence has shown that HSCs still maintain a certain level of mitochondrial activity in quiescence, and exhibit high mitochondrial membrane potential, which both support proper HSC function. Since glycolysis and the tricarboxylic acid (TCA) cycle are not directly connected in HSCs, other nutrient pathways, such as amino acid and fatty acid metabolism, generate acetyl-CoA and provide it to the TCA cycle. In this review, we discuss recent insights into the regulatory roles of cellular metabolism in HSCs. Understanding the metabolic requirements of healthy HSCs is of critical importance to the development of new therapies for hematological disorders.

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The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage

Cited by 46 publications

References 91 publications

Progenitor-intrinsic Metabolic Sensing Promotes Hematopoietic Homeostasis

Progenitor-intrinsic Metabolic Sensing Promotes Hematopoietic Homeostasis

Antigen receptor stimulation drives selection against pathogenic mtDNA variants that dysregulate lymphocyte responses

Metabolic Regulation of Hematopoietic Stem Cells

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