bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–10–24
nine papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect.
  2. Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters.
  3. TIM-3 in Leukemia; Immune Response and Beyond.
  4. Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.
  5. Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia.
  6. Mitochondrial Contributions to Hematopoietic Stem Cell Aging.
  7. The Intersection of Purine and Mitochondrial Metabolism in Cancer.
  8. Metabolic Acidosis in Leukemia.
  9. VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges.
  1. Oncogene. 2021 Oct 19.
    Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect.
    Jianong Zhang, Liang Zhang, Ji Nie, Yan Lin, Yao Li, Wei Xu, Jian-Yuan Zhao, Shi-Min Zhao, Chenji Wang.
      Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that connects the Ca2+-dependent signalling to multiple cellular responses. Calcineurin inhibitors (CNIs) have been widely used to suppress immune response in allograft patients. However, CNIs significantly increase cancer incidence in transplant recipients compared with the general population. Accumulating evidence suggests that CNIs may promote the malignant transformation of cancer cells in addition to its role in immunosuppression, but the underlying mechanisms remain poorly understood. Here, we show that calcineurin interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme that connects two key metabolic pathways of cells, glycolysis and the tricarboxylic acid cycle. Mitochondrial-localized calcineurin dephosphorylates PDHA1 at Ser232, Ser293 and Ser300, and thus enhances PDC enzymatic activity, remodels cellular glycolysis and oxidative phosphorylation, and suppresses cancer cell proliferation. Hypoxia attenuates mitochondrial translocation of calcineurin to promote PDC inactivation. Moreover, CNIs promote metabolic remodelling and the Warburg effect by blocking calcineurin-mediated PDC activation in cancer cells. Our findings indicate that calcineurin is a critical regulator of mitochondrial metabolism and suggest that CNIs may promote tumorigenesis through inhibition of the calcineurin-PDC pathway.
    DOI:  https://doi.org/10.1038/s41388-021-02065-0
  2. Biology (Basel). 2021 Oct 04. pii: 1000. [Epub ahead of print]10(10):
    Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters.
    Frédéric Bouillaud, Noureddine Hammad, Laurent Schwartz.
      Cellular bioenergetics requires an intense ATP turnover that is increased further by hypermetabolic states caused by cancer growth or inflammation. Both are associated with metabolic alterations and, notably, enhancement of the Warburg effect (also known as aerobic glycolysis) of poor efficiency with regard to glucose consumption when compared to mitochondrial respiration. Therefore, beside this efficiency issue, other properties of these two pathways should be considered to explain this paradox: (1) biosynthesis, for this only indirect effect should be considered, since lactate release competes with biosynthetic pathways in the use of glucose; (2) ATP production, although inefficient, glycolysis shows other advantages when compared to mitochondrial respiration and lactate release may therefore reflect that the glycolytic flux is higher than required to feed mitochondria with pyruvate and glycolytic NADH; (3) Oxygen supply becomes critical under hypermetabolic conditions, and the ATP/O2 ratio quantifies the efficiency of oxygen use to regenerate ATP, although aerobic metabolism remains intense the participation of anaerobic metabolisms (lactic fermentation or succinate generation) could greatly increase ATP/O2 ratio; (4) time and space constraints would explain that anaerobic metabolism is required while the general metabolism appears oxidative; and (5) active repression of respiration by glycolytic intermediates, which could ensure optimization of glucose and oxygen use.
    Keywords:  ATP; cancer; energy metabolism; glycolysis; inflammation; lactic fermentation; mitochondria
    DOI:  https://doi.org/10.3390/biology10101000
  3. Front Oncol. 2021 ;11 753677
    TIM-3 in Leukemia; Immune Response and Beyond.
    Mahnaz Rezaei, Jiaxiong Tan, Chengwu Zeng, Yangqiu Li, Mazdak Ganjalikhani-Hakemi.
      T cell immunoglobulin and mucin domain 3 (TIM-3) expression on malignant cells has been reported in some leukemias. In myelodysplastic syndrome (MDS), increased TIM-3 expression on TH1 cells, regulatory T cells, CD8+ T cells, and hematopoietic stem cells (HSCs), which play a role in the proliferation of blasts and induction of immune escape, has been reported. In AML, several studies have reported overexpression of TIM-3 on leukemia stem cells (LSCs) but not on healthy HSCs. Overexpression of TIM-3 on exhausted CD4+ and CD8+ T cells and leukemic cells in CML, ALL, and CLL patients could be a prognostic risk factor for poor therapeutic response and relapse in patients. Currently, several TIM-3 inhibitors are used in clinical trials for leukemias, and some have shown encouraging response rates for MDS and AML treatment. For AML immunotherapy, blockade TIM-3 may have dual effects: directly inhibiting AML cell proliferation and restoring T cell function. However, blockade of PD-1 and TIM-3 fails to restore the function of exhausted CD8+ T cells in the early clinical stages of CLL, indicating that the effects of TIM-3 blockade may be different in AML and other leukemias. Thus, further studies are required to evaluate the efficacy of TIM-3 inhibitors in different types and stages of leukemia. In this review, we summarize the biological functions of TIM-3 and its contribution as it relates to leukemias. We also discuss the effects of TIM-3 blockade in hematological malignancies and clinical trials of TIM-3 for leukemia therapy.
    Keywords:  TIM-3; acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphoblastic leukemia; chronic myeloid leukemia; myelodysplastic syndrome
    DOI:  https://doi.org/10.3389/fonc.2021.753677
  4. Cancers (Basel). 2021 Oct 19. pii: 5243. [Epub ahead of print]13(20):
    Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.
    Marie Sabatier, Emeline Boet, Sonia Zaghdoudi, Nathan Guiraud, Alexis Hucteau, Nathaniel Polley, Guillaume Cognet, Estelle Saland, Laura Lauture, Thomas Farge, Ambrine Sahal, Vera Pancaldi, Emeline Chu-Van, Florence Castelli, Sarah Bertoli, Pierre Bories, Christian Récher, Héléna Boutzen, Véronique Mansat-De Mas, Lucille Stuani, Jean-Emmanuel Sarry.
      Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.
    Keywords:  AML; ATRA; CEBPα; IDH; VDR; differentiation; vitamin D
    DOI:  https://doi.org/10.3390/cancers13205243
  5. Blood Cancer Discov. 2020 Sep;1(2): 134-145
    Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia.
    Catriona Jamieson, Giovanni Martinelli, Cristina Papayannidis, Jorge E Cortes.
      Targeting Hedgehog (Hh) pathway components, such as Smoothened (SMO), is a developing strategy for the treatment of acute myeloid leukemia (AML) and for overcoming relapsed/refractory forms of this disease. Several SMO inhibitors are in clinical development for the treatment of various tumor types and the results from some clinical trials in AML have been reported. This review will discuss the role of Hh signaling in AML pathogenesis, describe the preclinical and clinical development of Hh pathway inhibitors for the treatment of AML, and examine the current evidence on Hh pathway inhibitor resistance and the implications for treatment selection in AML.
    Significance: In acute myeloid leukemia (AML), components of the Hedgehog (Hh) signaling pathway, such as Smoothened (SMO), have been implicated in the development, maintenance, and expansion of leukemic stem cells (LSC), as well as sensitization to chemotherapy and the development of drug resistance in AML. Observations in preclinical studies of AML, as well as from samples of patients with AML, demonstrate that Hh pathway inhibitors act primarily on the stem cell pathway as differentiation agents. The current data for hematologic malignancies indicate the potential for a synergistic effect when a Hh pathway inhibitor is administered in combination with chemotherapy or investigational agents. It is thought that Hh pathway inhibitors act as agents that reduce LSC dormancy and promote LSC differentiation, thus the newly dividing LSCs can then be targeted by other chemotherapeutic drugs.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0007
  6. Int J Mol Sci. 2021 Oct 15. pii: 11117. [Epub ahead of print]22(20):
    Mitochondrial Contributions to Hematopoietic Stem Cell Aging.
    Claudia Morganti, Keisuke Ito.
      Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging. In the hematopoietic system, aging is linked to imbalanced immune response and reduced regenerative capacity in hematopoietic stem cells (HSCs), as well as an increased predisposition to a spectrum of diseases, including myelodysplastic syndrome and acute myeloid leukemia. Myeloid-biased differentiation and loss of polarity are distinct features of aged HSCs, which generally exhibit enhanced mitochondrial oxidative phosphorylation and increased production of reactive oxygen species (ROS), suggesting a direct role for mitochondria in the degenerative process. Here, we provide an overview of current knowledge of the mitochondrial mechanisms that contribute to age-related phenotypes in HSCs. These include mitochondrial ROS production, alteration/activation of mitochondrial metabolism, the quality control pathway of mitochondria, and inflammation. Greater understanding of the key machineries of HSC aging will allow us to identify new therapeutic targets for preventing, delaying, or even reversing aspects of this process.
    Keywords:  ROS; aging; hematopoiesis; hematopoietic stem cell; inflammation; mitochondrial metabolism; stem cell exhaustion
    DOI:  https://doi.org/10.3390/ijms222011117
  7. Cells. 2021 Sep 30. pii: 2603. [Epub ahead of print]10(10):
    The Intersection of Purine and Mitochondrial Metabolism in Cancer.
    Humberto De Vitto, Danushka B Arachchige, Brian C Richardson, Jarrod B French.
      Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.
    Keywords:  amino acids; cancers; metabolic reprogramming; mitochondrial metabolism; purines
    DOI:  https://doi.org/10.3390/cells10102603
  8. Cureus. 2021 Sep;13(9): e17732
    Metabolic Acidosis in Leukemia.
    Jaskamal Padda, Khizer Khalid, Varsha Kakani, Ayden Charlene Cooper, Gutteridge Jean-Charles.
      In 2020, the incidence of leukemia was 474,519 with 311,594 mortality worldwide. In 2021, the American Cancer Society (ACS) has estimated 61,090 new cases of leukemia to occur within the United States. It has also been reported that the most common cause of death in children from one to fourteen years old is oncological, with leukemia being the most frequent cause. A phenomenon known as the Warburg effect has been affiliated with cancer. The Warburg effect is a metabolic abnormality of lactic acidosis in malignancies, with most cases presenting as hematological malignancies such as leukemia. Although many theories have been formulated to clarify the role of the Warburg effect, the exact role still remains uncertain. Four suggested theories on why the Warburg effect happens to include cell signaling, adenosine triphosphate (ATP) synthesis, biosynthesis, and the tumor microenvironment. The Warburg effect occurs in leukemia with the help of enzymes such as pyruvate kinases M2 (PKM2), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 1 (PDK1), and fibroblast growth factor receptor 1 (FGFR1). In this literature, we explain the proposed hypotheses of the Warburg effect, along with the molecular mechanism of how leukemia is able to produce lactic acid, with the intent to better understand this phenomenon.
    Keywords:  atp synthesis; lactic acidosis; leukemia; metabolic acidosis; warburg effect
    DOI:  https://doi.org/10.7759/cureus.17732
  9. Front Physiol. 2021 ;12 742839
    VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges.
    Kareem A Heslop, Veronica Milesi, Eduardo N Maldonado.
      Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.
    Keywords:  Warburg; cancer; glycolysis; metabolic flexibility; metabolic reprogramming; metabolism; mitochondria; voltage dependent anion channels
    DOI:  https://doi.org/10.3389/fphys.2021.742839
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