bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–02–21
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche.
  2. Humanized CD19-targeted chimeric antigen receptor T (CAR-T) cells for relapsed/refractory pediatric acute lymphoblastic leukemia.
  3. A cold-stress-inducible PERK/OGT axis controls TOM70-assisted mitochondrial protein import and cristae formation.
  4. Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.
  5. Biofunction of Polydopamine Coating in Stem Cell Culture.
  6. LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells.
  7. The evolving landscape of immunotherapy in solid tumors.
  8. Mitochondrial Ion Channels of the Inner Membrane and Their Regulation in Cell Death Signaling.
  9. Editorial: Metabolic Regulation of Stem Cells and Tissue Growth.
  10. Mitochondrial and metabolic pathways regulate nuclear gene expression to control differentiation, stem cell function, and immune response in leukemia.
  1. Regen Ther. 2021 Jun;17 8-12
    Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche.
    Tadahito Yasuda, Takatsugu Ishimoto, Hideo Baba.
      Recent studies have revealed that cancer stem cells (CSCs) undergo metabolic alterations that differentiate them from non-CSCs. Inhibition of specific metabolic pathways in CSCs has been conducted to eliminate the CSC population in many types of cancer. However, there is conflicting evidence about whether CSCs depend on glycolysis or mitochondrial oxidative phosphorylation (OXPHOS) to maintain their stem cell properties. This review summarizes the latest knowledge regarding CSC-specific metabolic alterations and offers recent evidence that the surrounding microenvironments may play an important role in the maintenance of CSC properties.
    Keywords:  ALDH, aldehyde dehydrogenase; ATP, adenosine triphosphate; CD44v, CD44 variant isoform; CSCs; CSCs, cancer stem cells; EMT, epithelial–mesenchymal transition; EVs, extracellular vesicles; FAO, fatty acid oxidation; FBP1, fructose-1,6-biphosphatase 1; GLUT1, glucose transporter 1; GP6, glucose-6-phosphate; Glycolysis; HCC, hepatocellular carcinoma; HIF1a, hypoxia inducible factor 1a; IMP2, insulin-like growth factor 2; IncRNAs, long noncoding RNAs; LSCs, leukemia stem cells; Mitochondrial OXPHOS; NRF2, nuclear factor erythroid 2–related factor 2; OXPHOS, oxidative phosphorylation; PDK1, pyruvate dehydrogenase kinase 1; PPP, pentose phosphate pathway; ROS; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; Stromal niche; TCA, tricarboxylic acid; TICs, tumor initiating stem-like cells; mTORC1, mammalian target of rapamycin complex 1
    DOI:  https://doi.org/10.1016/j.reth.2021.01.005
  2. Am J Hematol. 2021 Feb 13.
    Humanized CD19-targeted chimeric antigen receptor T (CAR-T) cells for relapsed/refractory pediatric acute lymphoblastic leukemia.
    Shiyuan Wang, Xue Wang, Chunying Ye, Hai Cheng, Ming Shi, Wei Chen, Kunming Qi, Gang Wang, Qingyun Wu, Lingyu Zeng, Zhenyu Li, Guangjun Jing, Junnian Zheng, Kailin Xu, Jiang Cao.
      
    DOI:  https://doi.org/10.1002/ajh.26123
  3. Cell Metab. 2021 Feb 09. pii: S1550-4131(21)00013-9. [Epub ahead of print]
    A cold-stress-inducible PERK/OGT axis controls TOM70-assisted mitochondrial protein import and cristae formation.
    Pedro Latorre-Muro, Katherine E O'Malley, Christopher F Bennett, Elizabeth A Perry, Eduardo Balsa, Clint D J Tavares, Mark Jedrychowski, Steven P Gygi, Pere Puigserver.
      The architecture of cristae provides a spatial mitochondrial organization that contains functional respiratory complexes. Several protein components including OPA1 and MICOS complex subunits organize cristae structure, but upstream regulatory mechanisms are largely unknown. Here, in vivo and in vitro reconstitution experiments show that the endoplasmic reticulum (ER) kinase PERK promotes cristae formation by increasing TOM70-assisted mitochondrial import of MIC19, a critical subunit of the MICOS complex. Cold stress or β-adrenergic stimulation activates PERK that phosphorylates O-linked N-acetylglucosamine transferase (OGT). Phosphorylated OGT glycosylates TOM70 on Ser94, enhancing MIC19 protein import into mitochondria and promoting cristae formation and respiration. In addition, PERK-activated OGT O-GlcNAcylates and attenuates CK2α activity, which mediates TOM70 Ser94 phosphorylation and decreases MIC19 mitochondrial protein import. We have identified a cold-stress inter-organelle PERK-OGT-TOM70 axis that increases cell respiration through mitochondrial protein import and subsequent cristae formation. These studies have significant implications in cellular bioenergetics and adaptations to stress conditions.
    Keywords:  MIC19; PERK-OGT axis; TOM70; brown adipocytes; cold stress; cristae biogenesis; mitochondrial protein import; respiration
    DOI:  https://doi.org/10.1016/j.cmet.2021.01.013
  4. Cell Rep. 2021 Jan 26. pii: S2211-1247(20)31659-4. [Epub ahead of print]34(4): 108670
    Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.
    Qingfei Jiang, Jane Isquith, Luisa Ladel, Adam Mark, Frida Holm, Cayla Mason, Yudou He, Phoebe Mondala, Isabelle Oliver, Jessica Pham, Wenxue Ma, Eduardo Reynoso, Shawn Ali, Isabella Jamieson Morris, Raymond Diep, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda Birmingham, Sanja Coso, Gabriel Pineda, Leslie Crews, Mary E Donohoe, J Craig Venter, Thomas Whisenant, Ruben A Mesa, Ludmil B Alexandrov, Kathleen M Fisch, Catriona Jamieson.
      Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.
    Keywords:  Enter keywords here
    DOI:  https://doi.org/10.1016/j.celrep.2020.108670
  5. ACS Appl Mater Interfaces. 2021 Feb 17.
    Biofunction of Polydopamine Coating in Stem Cell Culture.
    Zijun Deng, Weiwei Wang, Xun Xu, Yan Nie, Yue Liu, Oliver E C Gould, Nan Ma, Andreas Lendlein.
      High levels of reactive oxygen species (ROS) during stem cell expansion often lead to replicative senescence. Here, a polydopamine (PDA)-coated substrate was used to scavenge extracellular ROS for mesenchymal stem cell (MSC) expansion. The PDA-coated substrate could reduce the oxidative stress and mitochondrial damage in replicative senescent MSCs. The expression of senescence-associated β-galactosidase of MSCs from three human donors (both bone marrow- and adipose tissue-derived) was suppressed on PDA. The MSCs on the PDA-coated substrate showed a lower level of interleukin 6 (IL-6), one of the senescence-associated inflammatory components. Cellular senescence-specific genes, such as p53 and p21, were downregulated on the PDA-coated substrate, while the stemness-related gene, OCT4, was upregulated. The PDA-coated substrate strongly promoted the proliferation rate of MSCs, while the stem cell character and differentiation potential were retained. Large-scale expansion of stem cells would greatly benefit from the PDA-coated substrate.
    Keywords:  ROS; cellular senescence; mesenchymal stem cells; polydopamine; proliferation
    DOI:  https://doi.org/10.1021/acsami.0c22565
  6. Nat Commun. 2021 02 16. 12(1): 1065
    LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells.
    S S Höpner, Ana Raykova, R Radpour, M A Amrein, D Koller, G M Baerlocher, C Riether, A F Ochsenbein.
      The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.
    DOI:  https://doi.org/10.1038/s41467-021-21317-x
  7. J Surg Oncol. 2021 Mar;123(3): 798-806
    The evolving landscape of immunotherapy in solid tumors.
    Jessica M Keilson, Hannah M Knochelmann, Chrystal M Paulos, Ragini R Kudchadkar, Michael C Lowe.
      While surgical resection, local and cytotoxic therapies have long formed the basis of cancer care, immunotherapy now plays a key role in supplementing and even replacing these agents in the first line. Here we review the early success of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 blockade and discuss biomarkers of therapeutic response. We next highlight a select group of novel targets in Phase III trials both as monotherapies and in combination with PD-1 inhibitors. Finally, we discuss innovations which seek to improve outcomes in therapy-resistant solid tumors.
    Keywords:  cancer; immunotherapy; solid tumors; tumor immunology
    DOI:  https://doi.org/10.1002/jso.26416
  8. Front Cell Dev Biol. 2020 ;8 620081
    Mitochondrial Ion Channels of the Inner Membrane and Their Regulation in Cell Death Signaling.
    Andrea Urbani, Elena Prosdocimi, Andrea Carrer, Vanessa Checchetto, Ildikò Szabò.
      Mitochondria are bioenergetic organelles with a plethora of fundamental functions ranging from metabolism and ATP production to modulation of signaling events leading to cell survival or cell death. Ion channels located in the outer and inner mitochondrial membranes critically control mitochondrial function and, as a consequence, also cell fate. Opening or closure of mitochondrial ion channels allow the fine-tuning of mitochondrial membrane potential, ROS production, and function of the respiratory chain complexes. In this review, we critically discuss the intracellular regulatory factors that affect channel activity in the inner membrane of mitochondria and, indirectly, contribute to cell death. These factors include various ligands, kinases, second messengers, and lipids. Comprehension of mitochondrial ion channels regulation in cell death pathways might reveal new therapeutic targets in mitochondria-linked pathologies like cancer, ischemia, reperfusion injury, and neurological disorders.
    Keywords:  apoptosis; cell death; cell signaling; ion channel; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2020.620081
  9. Front Mol Neurosci. 2020 ;13 625606
    Editorial: Metabolic Regulation of Stem Cells and Tissue Growth.
    Christian Lange, Francesco Bifari.
      
    Keywords:  angiogenesis; cell metabolism; metabolic fingerprint; metabolic flux analysis; nutrient; oxygen; regenerative medicine; stem cell differentiation and proliferation
    DOI:  https://doi.org/10.3389/fnmol.2020.625606
  10. Cancer Discov. 2021 Jan 27. pii: candisc.1227.2020. [Epub ahead of print]
    Mitochondrial and metabolic pathways regulate nuclear gene expression to control differentiation, stem cell function, and immune response in leukemia.
    Grace Egan, Dilshad H Khan, Jong Bok Lee, Sara Mirali, Li Zhang, Aaron D Schimmer.
      Mitochondria are involved in many biological processes including cellular homeostasis, energy generation and apoptosis. Moreover, mitochondrial and metabolic pathways are interconnected with gene expression to regulate cellular functions such as cell growth, survival, differentiation and immune recognition. Metabolites and mitochondrial enzymes regulate chromatin modifying-enzymes, chromatin remodeling, and transcription regulators. Deregulation of mitochondrial pathways and metabolism leads to alterations in gene expression that promotes cancer development, progression and evasion of the immune system. This review highlights how mitochondrial and metabolic pathways function as a central mediator to control gene expression, specifically on stem cell functions, differentiation and immune response in leukemia.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1227
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