bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–12–12
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. The Importance of Cellular Metabolic Pathways in Pathogenesis and Selective Treatments of Hematological Malignancies.
  2. Preclinical Evaluation of CD64 As a Potential Target For CAR-T-cell Therapy For Acute Myeloid Leukemia.
  3. Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy.
  4. Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.
  5. Immunotherapy for Acute Myeloid Leukemia: Allogeneic hematopoietic cell transplantation is here to stay.
  6. Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives.
  7. What is the role of the bone marrow microenvironment in AML?
  8. Adhesion Molecules Involved in Stem Cell Niche Retention During Normal Haematopoiesis and in Acute Myeloid Leukaemia.
  9. Prosurvival IL-7-Stimulated Weak Strength of mTORC1-S6K Controls T Cell Memory via Transcriptional FOXO1-TCF1-Id3 and Metabolic AMPKα1-ULK1-ATG7 Pathways.
  10. ROS activated prodrug for ALDH overexpressed cancer stem cells.
  11. Promyelocytic Leukemia Protein (PML) and Stem Cells: from cancer to pluripotency.
  12. Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3.
  1. Front Oncol. 2021 ;11 767026
    The Importance of Cellular Metabolic Pathways in Pathogenesis and Selective Treatments of Hematological Malignancies.
    Mojdeh Soltani, Yue Zhao, Zhijia Xia, Mazdak Ganjalikhani Hakemi, Alexandr V Bazhin.
      Despite recent advancements in the treatment of hematologic malignancies and the emergence of newer and more sophisticated therapeutic approaches such as immunotherapy, long-term overall survival remains unsatisfactory. Metabolic alteration, as an important hallmark of cancer cells, not only contributes to the malignant transformation of cells, but also promotes tumor progression and metastasis. As an immune-escape mechanism, the metabolic adaptation of the bone marrow microenvironment and leukemic cells is a major player in the suppression of anti-leukemia immune responses. Therefore, metabolic rewiring in leukemia would provide promising opportunities for newer therapeutic interventions. Several therapeutic agents which affect essential bioenergetic pathways in cancer cells including glycolysis, β-oxidation of fatty acids and Krebs cycle, or anabolic pathways such as lipid biosynthesis and pentose phosphate pathway, are being tested in various types of cancers. So far, numerous preclinical or clinical trial studies using such metabolic agents alone or in combination with other remedies such as immunotherapy are in progress and have demonstrated promising outcomes. In this review, we aim to argue the importance of metabolic alterations and bioenergetic pathways in different types of leukemia and their vital roles in disease development. Designing treatments based on targeting leukemic cells vulnerabilities, particularly in nonresponsive leukemia patients, should be warranted.
    Keywords:  acute lymphocytic leukemia; acute myeloid leukemia; cellular metabolism; chronic lymphocytic leukemia; chronic myeloid leukemia; immunometabolism
    DOI:  https://doi.org/10.3389/fonc.2021.767026
  2. J Immunother. 2021 Dec 06.
    Preclinical Evaluation of CD64 As a Potential Target For CAR-T-cell Therapy For Acute Myeloid Leukemia.
    Xiaolei Sun, Guoling Wang, Shiyu Zuo, Qing Niu, Xiaoli Chen, Xiaoming Feng.
      The relapsed and refractory acute myeloid leukemia (AML) patients receiving traditional chemotherapies have poor survival rate. Chimeric antigen receptor (CAR)-modified T cells have demonstrated remarkable effectiveness against some malignancies. However, most of CAR-Ts targeting the candidate proteins on AML cells induce hematopoietic cell suppression. Because of extensive heterogeneity among different types of AML, it is essential to expand the choice of target antigen for the CAR-T treatment of AML. CD64 (FcγRI) is a transmembrane protein with broad expression on various types of AML cells, especially monocytic AML cells, but it is absent on hematopoietic stem cells (HSCs) and most of nonmonocytes. Here, we found that some types of AML patients showed the homogeneous high-level expression of CD64. So, we created a CAR-T targeting CD64 (64bbz) and further verified its high efficiency for eradicating CD64+AML cells. In addition, 64bbz showed no cytotoxicity to HSCs. Overall, we developed a new treatment option for AML by using CD64 CAR-T cells while avoiding ablation of HSCs.
    DOI:  https://doi.org/10.1097/CJI.0000000000000406
  3. Cancers (Basel). 2021 Nov 24. pii: 5912. [Epub ahead of print]13(23):
    Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy.
    Angèle Luby, Marie-Clotilde Alves-Guerra.
      Over the past decade, advances in cancer immunotherapy through PD1-PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.
    Keywords:  cancer; immune response; immunotherapy; metabolic drug; metabolism
    DOI:  https://doi.org/10.3390/cancers13235912
  4. FASEB J. 2022 Jan;36(1): e22094
    Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.
    Kelsey H Fisher-Wellman, James T Hagen, Miki Kassai, Li-Pin Kao, Margaret A M Nelson, Kelsey L McLaughlin, Hannah S Coalson, Todd E Fox, Su-Fern Tan, David J Feith, Mark Kester, Thomas P Loughran, David F Claxton, Myles C Cabot.
      Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. In the present work, we utilized acute myeloid leukemia (AML) cell lines, selected to be refractory to various chemotherapeutics, to explore the interplay between SL metabolism and mitochondrial biology supportive of multidrug resistance (MDR). In agreement with previous findings in cytarabine or daunorubicin resistant AML cells, relative to chemosensitive wildtype controls, HL-60 cells refractory to vincristine (HL60/VCR) presented with alterations in SL enzyme expression and lipidome composition. Such changes were typified by upregulated expression of various ceramide detoxifying enzymes, as well as corresponding shifts in ceramide, glucosylceramide, and sphingomyelin (SM) molecular species. With respect to mitochondria, despite consistent increases in both basal respiration and maximal respiratory capacity, direct interrogation of the oxidative phosphorylation (OXPHOS) system revealed intrinsic deficiencies in HL60/VCR, as well as across multiple MDR model systems. Based on the apparent requirement for augmented SL and mitochondrial flux to support the MDR phenotype, we explored a combinatorial therapeutic paradigm designed to target each pathway. Remarkably, despite minimal cytotoxicity in peripheral blood mononuclear cells (PBMC), co-targeting SL metabolism, and respiratory complex I (CI) induced synergistic cytotoxicity consistently across multiple MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.
    Keywords:  HL-60 cells; acute myeloid leukemia; chemotherapy resistance; mitochondrial bioenergetics; sphingolipids; vincristine
    DOI:  https://doi.org/10.1096/fj.202101194RRR
  5. Leuk Res. 2021 Oct 21. pii: S0145-2126(21)01733-1. [Epub ahead of print]112 106732
    Immunotherapy for Acute Myeloid Leukemia: Allogeneic hematopoietic cell transplantation is here to stay.
    Guneet Kaleka, Gary Schiller.
      Acute Myeloid Leukemia (AML) represents 1 % of all new cancer diagnosis made annually in the US and has a five-year survival of 30 %. Traditional treatment includes aggressive induction therapy followed by consolidation therapy that may include a hematopoietic stem cell transplant (HSCT). Thus far, HSCT remains the only potentially curative therapy for many patients with AML owing to the graft-versus-leukemia effect elicited by this treatment. The use of novel therapies, specifically immunotherapy, in the treatment of AML has been limited by the lack of appropriate target antigens, therapy associated toxicities and variable success with treatment. Antigenic variability on leukemia cells and the sharing of antigens by malignant and non-malignant cells makes the identification of appropriate antigens problematic. While studies with immunotherapeutic agents are underway, prior investigations have demonstrated a mixed response with some studies prematurely discontinued due to associated toxicities. This review presents a discussion of the envisioned role of immunotherapy in the treatment of AML in the setting of mixed therapeutic success and potentially lethal toxicities.
    Keywords:  AML; Acute Myeloid Leukemia; HSCT; Hematopoietic stem cell transplant; Immunotherapy
    DOI:  https://doi.org/10.1016/j.leukres.2021.106732
  6. Int J Mol Sci. 2021 Nov 23. pii: 12620. [Epub ahead of print]22(23):
    Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives.
    Salvatore Passarella, Avital Schurr, Piero Portincasa.
      Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment.
    Keywords:  L-lactate; gluconeogenesis; glycolysis; mitochondrial shuttles; mitochondrial transport; phosphoenolpyruvate
    DOI:  https://doi.org/10.3390/ijms222312620
  7. Best Pract Res Clin Haematol. 2021 Dec;pii: S1521-6926(21)00093-1. [Epub ahead of print]34(4): 101328
    What is the role of the bone marrow microenvironment in AML?
    Nirupama Mulherkar, David T Scadden.
      Acute myeloid leukemia (AML) continues to be associated with relapse and resistance to chemotherapy. The bone marrow microenvironment in AML has been shown to regulate responsiveness to chemotherapy and to support disease progression. This review summarizes some recent experimental insights into the crucial role of the bone marrow microenvironment in AML and persistence after chemotherapy.
    Keywords:  AML; Acute myeloid leukemia; Bone marrow microenvironment; Chemotherapy persistence; Hematopoietic stem cells; Leukemic stem cells; Metabolism; Niche; mTORC1
    DOI:  https://doi.org/10.1016/j.beha.2021.101328
  8. Front Immunol. 2021 ;12 756231
    Adhesion Molecules Involved in Stem Cell Niche Retention During Normal Haematopoiesis and in Acute Myeloid Leukaemia.
    Julien M P Grenier, Céline Testut, Cyril Fauriat, Stéphane J C Mancini, Michel Aurrand-Lions.
      In the bone marrow (BM) of adult mammals, haematopoietic stem cells (HSCs) are retained in micro-anatomical structures by adhesion molecules that regulate HSC quiescence, proliferation and commitment. During decades, researchers have used engraftment to study the function of adhesion molecules in HSC's homeostasis regulation. Since the 90's, progress in genetically engineered mouse models has allowed a better understanding of adhesion molecules involved in HSCs regulation by BM niches and raised questions about the role of adhesion mechanisms in conferring drug resistance to cancer cells nested in the BM. This has been especially studied in acute myeloid leukaemia (AML) which was the first disease in which the concept of cancer stem cell (CSC) or leukemic stem cells (LSCs) was demonstrated. In AML, it has been proposed that LSCs propagate the disease and are able to replenish the leukemic bulk after complete remission suggesting that LSC may be endowed with drug resistance properties. However, whether such properties are due to extrinsic or intrinsic molecular mechanisms, fully or partially supported by molecular crosstalk between LSCs and surrounding BM micro-environment is still matter of debate. In this review, we focus on adhesion molecules that have been involved in HSCs or LSCs anchoring to BM niches and discuss if inhibition of such mechanism may represent new therapeutic avenues to eradicate LSCs.
    Keywords:  acute myeloid leukaemia; adhesion; bone marrow; haematopoiesis; haematopoietic stem cell; leukemic stem cell
    DOI:  https://doi.org/10.3389/fimmu.2021.756231
  9. J Immunol. 2021 Dec 06. pii: ji2100452. [Epub ahead of print]
    Prosurvival IL-7-Stimulated Weak Strength of mTORC1-S6K Controls T Cell Memory via Transcriptional FOXO1-TCF1-Id3 and Metabolic AMPKα1-ULK1-ATG7 Pathways.
    Aizhang Xu, Scot C Leary, Md Fahmid Islam, Zhaojia Wu, Kalpana Kalyanasundaram Bhanumathy, Anjuman Ara, Rajni Chibbar, Andrew Fleywald, Khawaja Ashfaque Ahmed, Jim Xiang.
      CD8+ memory T (TM) cells play a critical role in immune defense against infection. Two common γ-chain family cytokines, IL-2 and IL-7, although triggering the same mTORC1-S6K pathway, distinctly induce effector T (TE) cells and TM cells, respectively, but the underlying mechanism(s) remains elusive. In this study, we generated IL-7R-/and AMPKα1-knockout (KO)/OTI mice. By using genetic and pharmaceutical tools, we demonstrate that IL-7 deficiency represses expression of FOXO1, TCF1, p-AMPKα1 (T172), and p-ULK1 (S555) and abolishes T cell memory differentiation in IL-7R KO T cells after Listeria monocytogenesis rLmOVA infection. IL-2- and IL-7-stimulated strong and weak S6K (IL-2/S6Kstrong and IL-7/S6Kweak) signals control short-lived IL-7R-CD62L-KLRG1+ TE and long-term IL-7R+CD62L+KLRG1- TM cell formations, respectively. To assess underlying molecular pathway(s), we performed flow cytometry, Western blotting, confocal microscopy, and Seahorse assay analyses by using the IL-7/S6Kweak-stimulated TM (IL-7/TM) and the control IL-2/S6Kstrong-stimulated TE (IL-2/TE) cells. We determine that the IL-7/S6Kweak signal activates transcriptional FOXO1, TCF1, and Id3 and metabolic p-AMPKα1, p-ULK1, and ATG7 molecules in IL-7/TM cells. IL-7/TM cells upregulate IL-7R and CD62L, promote mitochondria biogenesis and fatty acid oxidation metabolism, and show long-term cell survival and functional recall responses. Interestingly, AMPKα1 deficiency abolishes the AMPKα1 but maintains the FOXO1 pathway and induces a metabolic switch from fatty acid oxidation to glycolysis in AMPKα1 KO IL-7/TM cells, leading to loss of cell survival and recall responses. Taken together, our data demonstrate that IL-7-stimulated weak strength of mTORC1-S6K signaling controls T cell memory via activation of transcriptional FOXO1-TCF1-Id3 and metabolic AMPKα1-ULK1-ATG7 pathways. This (to our knowledge) novel finding provides a new mechanism for a distinct IL-2/IL-7 stimulation model in T cell memory and greatly impacts vaccine development.
    DOI:  https://doi.org/10.4049/jimmunol.2100452
  10. Chem Commun (Camb). 2021 Dec 07.
    ROS activated prodrug for ALDH overexpressed cancer stem cells.
    Miae Won, Ji Hyeon Kim, Myung Sun Ji, Jong Seung Kim.
      Aldehyde dehydrogenase (ALDH), a cancer stem cell biomarker, is related to drug resistance. Co-treatment of anti-cancer drug (CPT) and ALDH inhibitor (DEAB) can overcome the drug resistance of cancer stem cells (CSCs) and finally cure cancers without relapse. We herein introduce a prodrug (DE-CPT) - consisting of 1,3-oxathiolane as an ROS responsive scaffold, and an aldehyde protecting group of DEAB - to deliver the CPT and DEAB upon reaction with ROS. From tests of the sphere-forming ability and CSC marker subpopulation, we found that DE-CPT efficiently decreases the CSCs population and kills the cancer cells.
    DOI:  https://doi.org/10.1039/d1cc05573a
  11. Int J Dev Biol. 2021 Oct 26.
    Promyelocytic Leukemia Protein (PML) and Stem Cells: from cancer to pluripotency.
    Amalia P Vogiatzoglou, Fabien Moretto, Maria Makkou, Joseph Papamatheakis, Androniki Kretsovali.
      The promyelocytic leukemia protein (PML) is the core organizer of the cognate nuclear bodies (PML-NBs). Through physical interaction or modification of diverse protein clients, PML-NBs regulate a multitude of - often antithetical- biological processes such as antiviral and stress response, inhibition of cell proliferation and autophagy, and promotion of apoptosis or senescence. Although PML was originally recognized as a tumor-suppressive factor, more recent studies revealed a "double faced" agent role for PML. Indeed PML displayed tumor cell pro-survival and pro-migratory functions via inhibition of migration suppressing molecules or promotion of transforming growth factor beta (TGF-β) mediated Epithelial-Mesenchymal Transition (EMT) that may promote cancer cell dissemination. In this line, PML was found to correlate with poor patient prognosis in distinct tumor contexts. Furthermore in the last decade, a number of publications have implicated PML in the physiology of normal or cancer stem cells (CSCs). Promyelocytic leukemia protein is activating fatty acid oxidation (FAO), a metabolic mechanism required for the asymmetric divisions and maintenance of hematopoietic stem cells (HSCs). In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), PML is required for maintenance of the naïve and acquisition of the induced pluripotency state respectively. Correspondingly, PML ablation causes significant morphological, gene expression and lineage choice changes. In this review, we focus on the mechanisms orchestrated by PML and PML-NBs in cancer and healthy stem cells from cell physiology to the regulation of chromatin dynamics.
    DOI:  https://doi.org/10.1387/ijdb.210154av
  12. Cancers (Basel). 2021 Dec 06. pii: 6142. [Epub ahead of print]13(23):
    Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3.
    Fatima Baker, Ibrahim H Polat, Khalil Abou-El-Ardat, Islam Alshamleh, Marlyn Thoelken, Daniel Hymon, Andrea Gubas, Sebastian E Koschade, Jonas B Vischedyk, Manuel Kaulich, Harald Schwalbe, Shabnam Shaid, Christian H Brandts.
      Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML.
    Keywords:  ATG3; acute myeloid leukemia; autophagy; autophagy inhibition; metabolic rewiring
    DOI:  https://doi.org/10.3390/cancers13236142
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