bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–03–19
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.
  2. Augmenting Venetoclax Activity Through Signal Transduction in AML.
  3. FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells.
  4. The TRIM31-paradox: an unexpected benefit for leukemia stem cells.
  5. Chemotherapeutic drugs elicit stemness and metabolic alteration to mediate acquired drug-resistant phenotype in acute myeloid leukemia cell lines.
  6. Estimation of energy pathway fluxes in cancer cells - Beyond the Warburg effect.
  7. Metabolic crosstalk between stromal and malignant cells in the bone marrow niche.
  8. Metabolic sensing and control in mitochondria.
  9. Editorial: Critical complications in pediatric oncology and hematopoietic cell transplant - how far we have come and how much further we must go.
  10. Role of amino acid metabolism in mitochondrial homeostasis.
  11. Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
  1. bioRxiv. 2023 Mar 01. pii: 2023.02.27.530273. [Epub ahead of print]
    Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.
    Mariam Murtadha, Miso Park, Yinghui Zhu, Enrico Caserta, Ada Alice Dona, Mahmoud Singer, Hawa Vahed, Theophilus Tasndoh, Asaul Gonzalez, Kevin Ly, James F Sanchez, Arnab Chowdhury, Alex Pozhitkov, Lucy Ghoda, Ling Li, Bin Zhang, Amrita Krishnan, Guido Marcucci, John Williams, Flavia Pichiorri.
      Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38 pos ), the presence of CD34 and lack of CD38 expression (CD34 pos CD38 neg ) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-γ induces CD38 upregulation in LSC-enriched CD34 pos CD38 neg AML blasts, but not in CD34 pos CD38 neg HSCs. To leverage the IFN-γ mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38 pos blasts. Activated CD4 pos and CD8 pos T cells not only kill AML blasts but also produce IFNγ, which leads to CD38 expression on CD34 pos CD38 neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38 neg and CD38 pos AML blasts, which culminates in LSC depletion.
    Statement of significance: This work represents a potential advancement in the treatment of AML, as it involves the release of IFN-γ by T cells to induce CD38 expression and thus sensitizing leukemia stem cells, which have been resistant to current treatment regimens, to CD38-directed T cell engagers.
    DOI:  https://doi.org/10.1101/2023.02.27.530273
  2. J Cell Signal. 2023 ;4(1): 1-12
    Augmenting Venetoclax Activity Through Signal Transduction in AML.
    Ian Michael Bouligny, Keri Renee Maher, Steven Grant.
      Venetoclax, a small-molecule B-cell lymphoma 2 (BCL-2) inhibitor, selectively eradicates leukemic stem cells (LSCs). While venetoclax has revolutionized the treatment of acute myeloid leukemia (AML), treatment failure and disease relapse are common. Mechanisms underlying venetoclax resistance are surprisingly heterogeneous. Venetoclax resistance encompasses a spectrum of genetic and epigenetic changes, with numerous pathways contributing to the upregulation of additional anti-apoptotic proteins. In this review, we address the mechanisms of venetoclax resistance in the context of signal transduction. We emphasize how aberrant cell signaling impairs apoptosis and predisposes to venetoclax failure. Commonly activated pathways, such as FLT3, PI3K/AKT/mTOR, and RAS, contribute to upregulated anti-apoptotic mediators and are frequently responsible for refractory disease or disease relapse. We highlight novel combination strategies aimed at disabling constitutively active signal transduction to augment response and overcome venetoclax resistance.
    Keywords:  Acute myeloid leukemia; Akt pathway; Apoptotic pathways; B-cell lymphoma 2; FMS-like tyrosine kinase 3; Isocitrate dehydrogenase 1; Isocitrate dehydrogenase 2; MAPK pathway cell signaling; Signal transduction cascades
    DOI:  https://doi.org/10.33696/signaling.4.085
  3. Blood Adv. 2023 Mar 17. pii: bloodadvances.2022008585. [Epub ahead of print]
    FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells.
    Francoise Levavasseur, Samia Oussous, Tuerdi Zubaidan, Olivier Kosmider, Frédéric Pendino, David Rombaut, Didier Bouscary, Michaela Fontenay, Evelyne Lauret, Isabelle Dusanter-Fourt.
      Transcription factor Forkhead box P1 (FOXP1) belongs to the same protein family as the FOXOs that are well-known regulators of murine hematopoietic stem progenitor cell (HSPC) maintenance by dampening oxidative stress. FOXP1 and FOXOs can play opposite or similar roles depending on cell context; they can cross-regulate each other's expression. In a previous study, we have shown that FOXP1 contributes to normal human HSP and acute myeloid leukemia (AML) cell growth. Here we investigated the role of FOXP1 in HSPCs and AML cell oxidative stress defense in human context. FOXP1 expression level was associated with inferior survival outcome of cytogenetically normal (CN) AML patients. FOXP1 knockdown enhanced superoxide anion levels of human committed CD34+CD38+ but not stem cell-enriched CD34+CD38- HSPCs, and AML cells in vitro. It triggered enhanced NRF2 activity and increased cell oxidative stress. FOXP1 had no impact on FOXO1/3/4 expression in these cells; genetic and pharmacological inhibition of FOXOs did not change superoxide anion levels of human HSPCs and AML cells. Also, FOXP1 antioxidant activity was independent of superoxide dismutase (SOD)1-2 or catalase expression changes. Instead, FOXP1 upregulated expression of the stress sensor SIRT1 by stabilizing SIRT1 protein. FOXP1 loss sensitized AML cells to chemotherapy. Altogether, this study identified FOXP1 as a new safeguard against myeloid progenitor oxidative stress, which works independently of FOXOs but through SIRT1, and contributes to AML chemoresistance. It proposes FOXP1 expression/activity as a promising target to overcome drug-resistance of AML HSPCs.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008585
  4. Haematologica. 2023 Mar 16.
    The TRIM31-paradox: an unexpected benefit for leukemia stem cells.
    Jasmin Straube, Steven W Lane.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.282622
  5. Leuk Res. 2023 Mar 03. pii: S0145-2126(23)00039-5. [Epub ahead of print]128 107054
    Chemotherapeutic drugs elicit stemness and metabolic alteration to mediate acquired drug-resistant phenotype in acute myeloid leukemia cell lines.
    Raveen Stephen Stallon Illangeswaran, Daniel Zechariah Paul Jebanesan, Kezia Kanimozhi Sivakumar, Rakhi Thalayattu Vidhyadharan, Bharathi M Rajamani, Nancy Beryl Janet, Ernest David, Shaji Ramachandran Velayudhan, Vikram Mathews, Poonkuzhali Balasubramanian.
      Chemotherapy resistance leading to disease relapse is a significant barrier in treating acute myeloid leukemia (AML). Metabolic adaptations have been shown to contribute to therapy resistance. However, little is known about whether specific therapies cause specific metabolic changes. We established cytarabine-resistant (AraC-R) and Arsenic trioxide-resistant (ATO-R) AML cell lines, displaying distinct cell surface expression and cytogenetic abnormalities. Transcriptomic analysis revealed a significant difference in the expression profiles of ATO-R and AraC-R cells. Geneset enrichment analysis showed AraC-R cells rely on OXPHOS, while ATO-R cells on glycolysis. ATO-R cells were also enriched for stemness gene signatures, whereas AraC-R cells were not. The mito stress and glycolytic stress tests confirmed these findings. The distinct metabolic adaptation of AraC-R cells increased sensitivity to the OXPHOS inhibitor venetoclax. Cytarabine resistance was circumvented in AraC-R cells by combining Ven and AraC. In vivo, ATO-R cells showed increased repopulating potential, leading to aggressive leukemia compared to the parental and AraC-R. Overall, our study shows that different therapies can cause different metabolic changes and that these metabolic dependencies can be used to target chemotherapy-resistant AML.
    Keywords:  AML; Acquired chemoresistance; FLT3-ITD; Metabolic adaptation
    DOI:  https://doi.org/10.1016/j.leukres.2023.107054
  6. Arch Biochem Biophys. 2023 Mar 09. pii: S0003-9861(23)00058-9. [Epub ahead of print]739 109559
    Estimation of energy pathway fluxes in cancer cells - Beyond the Warburg effect.
    Rafael Moreno-Sánchez, Diana Xochiquetzal Robledo-Cadena, Silvia Cecilia Pacheco-Velázquez, Jorge Luis Vargas Navarro, Joaquín Alberto Padilla-Flores, Sara Rodríguez-Enríquez.
      Glycolytic and respiratory fluxes were analyzed in cancer and non-cancer cells. The steady-state fluxes in energy metabolism were used to estimate the contributions of aerobic glycolytic and oxidative phosphorylation (OxPhos) pathways to the cellular ATP supply. The rate of lactate production - corrected for the fraction generated by glutaminolysis - is proposed as the appropriate way to estimate glycolytic flux. In general, the glycolytic rates estimated for cancer cells are higher than those found in non-cancer cells, as originally observed by Otto Warburg. The rate of basal or endogenous cellular O2 consumption corrected for non-ATP synthesizing O2 consumption, measured after inhibition by oligomycin (a specific, potent and permeable ATP synthase inhibitor), has been proposed as the appropriate way to estimate mitochondrial ATP synthesis-linked O2 flux or net OxPhos flux in living cells. Detecting non-negligible oligomycin-sensitive O2 consumption rates in cancer cells has revealed that the mitochondrial function is not impaired, as claimed by the Warburg effect. Furthermore, when calculating the relative contributions to cellular ATP supply, under a variety of environmental conditions and for different types of cancer cells, it was found that OxPhos pathway was the main ATP provider over glycolysis. Hence, OxPhos pathway targeting can be successfully used to block in cancer cells ATP-dependent processes such as migration. These observations may guide the re-design of novel targeted therapies.
    Keywords:  ATP supply In cancer cells; Glycolysis; Metastasis; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.abb.2023.109559
  7. Bone Rep. 2023 Jun;18 101669
    Metabolic crosstalk between stromal and malignant cells in the bone marrow niche.
    Hernán A Tirado, Nithya Balasundaram, Lotfi Laaouimir, Ayşegül Erdem, Nick van Gastel.
      Bone marrow is the primary site of blood cell production in adults and serves as the source of osteoblasts and osteoclasts that maintain bone homeostasis. The medullary microenvironment is also involved in malignancy, providing a fertile soil for the growth of blood cancers or solid tumors metastasizing to bone. The cellular composition of the bone marrow is highly complex, consisting of hematopoietic stem and progenitor cells, maturing blood cells, skeletal stem cells, osteoblasts, mesenchymal stromal cells, adipocytes, endothelial cells, lymphatic endothelial cells, perivascular cells, and nerve cells. Intercellular communication at different levels is essential to ensure proper skeletal and hematopoietic tissue function, but it is altered when malignant cells colonize the bone marrow niche. While communication often involves soluble factors such as cytokines, chemokines, and growth factors, as well as their respective cell-surface receptors, cells can also communicate by exchanging metabolic information. In this review, we discuss the importance of metabolic crosstalk between different cells in the bone marrow microenvironment, particularly concerning the malignant setting.
    Keywords:  Bone marrow; Bone metastasis; Cell metabolism; Cellular communication; Leukemia; Stromal cells
    DOI:  https://doi.org/10.1016/j.bonr.2023.101669
  8. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00119-3. [Epub ahead of print]83(6): 877-889
    Metabolic sensing and control in mitochondria.
    Yuyang Liu, Kıvanç Birsoy.
      Mitochondria are membrane-enclosed organelles with endosymbiotic origins, harboring independent genomes and a unique biochemical reaction network. To perform their critical functions, mitochondria must maintain a distinct biochemical environment and coordinate with the cytosolic metabolic networks of the host cell. This coordination requires them to sense and control metabolites and respond to metabolic stresses. Indeed, mitochondria adopt feedback or feedforward control strategies to restrain metabolic toxicity, enable metabolic conservation, ensure stable levels of key metabolites, allow metabolic plasticity, and prevent futile cycles. A diverse panel of metabolic sensors mediates these regulatory circuits whose malfunctioning leads to inborn errors of metabolism with mild to severe clinical manifestations. In this review, we discuss the logic and molecular basis of metabolic sensing and control in mitochondria. The past research outlined recurring patterns in mitochondrial metabolic sensing and control and highlighted key knowledge gaps in this organelle that are potentially addressable with emerging technological breakthroughs.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.016
  9. Front Oncol. 2023 ;13 1148321
    Editorial: Critical complications in pediatric oncology and hematopoietic cell transplant - how far we have come and how much further we must go.
    Asya Agulnik, Kris M Mahadeo, Marie E Steiner, Jennifer Ann McArthur.
      
    Keywords:  CAR (chimeric antigen receptor) T cells; hematopoietic cell transplant; pediatric cancer; pediatric critical care; pediatric oncology and hematology
    DOI:  https://doi.org/10.3389/fonc.2023.1148321
  10. Front Cell Dev Biol. 2023 ;11 1127618
    Role of amino acid metabolism in mitochondrial homeostasis.
    Qiaochu Li, Thorsten Hoppe.
      Mitochondria are central hubs for energy production, metabolism and cellular signal transduction in eukaryotic cells. Maintenance of mitochondrial homeostasis is important for cellular function and survival. In particular, cellular metabolic state is in constant communication with mitochondrial homeostasis. One of the most important metabolic processes that provide energy in the cell is amino acid metabolism. Almost all of the 20 amino acids that serve as the building blocks of proteins are produced or degraded in the mitochondria. The synthesis of the amino acids aspartate and arginine depends on the activity of the respiratory chain, which is essential for cell proliferation. The degradation of branched-chain amino acids mainly occurs in the mitochondrial matrix, contributing to energy metabolism, mitochondrial biogenesis, as well as protein quality control in both mitochondria and cytosol. Dietary supplementation or restriction of amino acids in worms, flies and mice modulates lifespan and health, which has been associated with changes in mitochondrial biogenesis, antioxidant response, as well as the activity of tricarboxylic acid cycle and respiratory chain. Consequently, impaired amino acid metabolism has been associated with both primary mitochondrial diseases and diseases with mitochondrial dysfunction such as cancer. Here, we present recent observations on the crosstalk between amino acid metabolism and mitochondrial homeostasis, summarise the underlying molecular mechanisms to date, and discuss their role in cellular functions and organismal physiology.
    Keywords:  TCA cycle; amino acid metabolism; amino acid recycling; lifespan; mitochondrial homeostasis; proteasome; respiratory chain
    DOI:  https://doi.org/10.3389/fcell.2023.1127618
  11. EMBO J. 2023 Mar 14. e111901
    Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
    Jennifer Ngo, Dong Wook Choi, Illana A Stanley, Linsey Stiles, Anthony J A Molina, Pei-Hsuan Chen, Ana Lako, Isabelle Chiao Han Sung, Rishov Goswami, Min-Young Kim, Nathanael Miller, Siyouneh Baghdasarian, Doyeon Kim-Vasquez, Anthony E Jones, Brett Roach, Vincent Gutierrez, Karel Erion, Ajit S Divakaruni, Marc Liesa, Nika N Danial, Orian S Shirihai.
      Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.
    Keywords:  CPT1; fatty acid oxidation; fission; fusion; mitochondrial dynamics
    DOI:  https://doi.org/10.15252/embj.2022111901
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