bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–06–12
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. [Identification of GPAT1-dependent mitochondrial metabolism as a novel therapeutic target for AML].
  2. Biting into a union of oncology and metabolism through leukemic stem cells.
  3. Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities.
  4. Novel mitochondria-targeting compounds selectively kill human leukemia cells.
  5. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy.
  6. Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.
  7. Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer mitochondrial drug, CPI-613.
  8. The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression.
  9. The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness.
  10. cancer cell de-differentiation: plasticity- driven stratagem for tumor metastasis and recurrence.
  11. Novel nanocarriers for silencing anti-phagocytosis CD47 marker in acute myeloid leukemia cells.
  12. Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle.
  1. Rinsho Ketsueki. 2022 ;63(5): 353-362
    [Identification of GPAT1-dependent mitochondrial metabolism as a novel therapeutic target for AML].
    Hidetoshi Irifune.
      Recent studies have demonstrated that cancer-specific metabolism plays a crucial role in a variety of malignancies, including acute myeloid leukemia (AML). To identify a novel therapeutic target for AML, we conducted a metabolite screen on AML cells and normal hematopoietic stem/progenitor cells (HSPCs) and detected that the metabolism of glycerol-3-phosphate (G3P) is reprogrammed in AML. Glycerol-3-phosphate acyltransferases (GPATs), the first and rate-limiting enzymes in the lipid biosynthesis pathway, convert G3P into lysophosphatidic acid (LPA). Among various GPAT isozymes, GPAT1 was highly expressed in AML cells and silencing it inhibited the cell growth of AML. GPAT1 is located on the outer membrane of the mitochondria and regulates mitochondrial fusion and oxidative phosphorylation (OXPHOS). Silencing GPAT1 promoted mitochondrial fission and reduced OXPHOS. In AML, the GPAT1 inhibitor also suppressed cell proliferation and mitochondrial metabolism. However, this inhibitor had no effect on normal hematopoiesis in vivo. In conclusion, these findings indicate that targeting GPAT1 may be a promising therapeutic strategy for AML, since it suppresses leukemia-specific metabolism without impairing normal HSPCs.
    Keywords:  Acute myeloid leukemia; Glycerol-3-phosphate acyltransferases 1; Mitochondria dynamics; Oxidative phosphorylation
    DOI:  https://doi.org/10.11406/rinketsu.63.353
  2. Cell Metab. 2022 Jun 07. pii: S1550-4131(22)00188-7. [Epub ahead of print]34(6): 801-802
    Biting into a union of oncology and metabolism through leukemic stem cells.
    Mickie Bhatia, Amro Elrafie.
      In this issue of Cell Metabolism, Liu et al. demonstrate that Prmt7 can regulate the onset and progression of leukemogenesis by inhibiting self-renewal capacity of leukemic stem cells (LSCs) as modeled in a murine version of chronic myeloid leukemia (CML).
    DOI:  https://doi.org/10.1016/j.cmet.2022.05.006
  3. Adv Sci (Weinh). 2022 Jun;9(16): 2105811
    Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities.
    Luwen Zhang, Qiong Zhao, Hui Cang, Ziqiang Wang, Xiaojia Hu, Ruolang Pan, Yang Yang, Ye Chen.
      Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient-derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation-dependent manner. Mechanistic studies identify that AML cell-derived exosomes play a vital role during the AML cell-mediated MSCs education/reprogramming process. Pre-administration of mice BM microenvironment with AML-derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML-derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome-based AML cells-MSCs communication. Collectively, the data show that AML-educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.
    Keywords:  acute myeloid leukemia (AML); cell‐derived exosomes; mesenchymal stromal cells (MSCs)
    DOI:  https://doi.org/10.1002/advs.202105811
  4. Leukemia. 2022 Jun 07.
    Novel mitochondria-targeting compounds selectively kill human leukemia cells.
    Svetlana B Panina, Jingqi Pei, Natalia Baran, Elissa Tjahjono, Shraddha Patel, Gheath Alatrash, Sergej Konoplev, Leonid A Stolbov, Vladimir V Poroikov, Marina Konopleva, Natalia V Kirienko.
      Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies commonly associated with treatment resistance, high risk of relapse, and mitochondrial dysregulation. We identified six mitochondria-affecting compounds (PS compounds) that exhibit selective cytotoxicity against AML cells in vitro. Structure-activity relationship studies identified six analogs from two original scaffolds that had over an order of magnitude difference between LD50 in AML and healthy peripheral blood mononuclear cells. Mechanistically, all hit compounds reduced ATP and selectively impaired both basal and ATP-linked oxygen consumption in leukemic cells. Compounds derived from PS127 significantly upregulated production of reactive oxygen species (ROS) in AML cells and triggered ferroptotic, necroptotic, and/or apoptotic cell death in AML cell lines and refractory/relapsed AML primary samples. These compounds exhibited synergy with several anti-leukemia agents in AML, acute lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML). Pilot in vivo efficacy studies indicate anti-leukemic efficacy in a MOLM14/GFP/LUC xenograft model, including extended survival in mice injected with leukemic cells pre-treated with PS127B or PS127E and in mice treated with PS127E at a dose of 5 mg/kg. These compounds are promising leads for development of future combinatorial therapeutic approaches for mitochondria-driven hematologic malignancies such as AML, ALL, and CML.
    DOI:  https://doi.org/10.1038/s41375-022-01614-0
  5. World J Stem Cells. 2022 Apr 26. 14(4): 267-286
    Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy.
    Qi Zhang, Wei Li.
      Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
    Keywords:  Amino acid metabolism; Cancer stem cell; Resistance; Self-renewal
    DOI:  https://doi.org/10.4252/wjsc.v14.i4.267
  6. Cancers (Basel). 2022 May 28. pii: 2681. [Epub ahead of print]14(11):
    Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.
    Debbie Piktel, Rajesh R Nair, Stephanie L Rellick, Werner J Geldenhuys, Karen H Martin, Michael D Craig, Laura F Gibson.
      The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL.
    Keywords:  ALL; drug resistance; lipid metabolism; metabolism
    DOI:  https://doi.org/10.3390/cancers14112681
  7. PLoS One. 2022 ;17(6): e0269620
    Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer mitochondrial drug, CPI-613.
    Moises O Guardado Rivas, Shawn D Stuart, Daniel Thach, Michael Dahan, Robert Shorr, Zuzana Zachar, Paul M Bingham.
      Clinical targeting of the altered metabolism of tumor cells has long been considered an attractive hypothetical approach. However, this strategy has yet to perform well clinically. Metabolic redundancy is among the limitations on effectiveness of many approaches, engendering intrinsic single-agent resistance or efficient evolution of such resistance. We describe new studies of the multi-target, tumor-preferential inhibition of the mitochondrial tricarboxylic acid (TCA) cycle by the first-in-class drug CPI-613® (devimistat). By suppressing the TCA hub, indispensable to many metabolic pathways, CPI-613 substantially reduces the effective redundancy of tumor catabolism. This TCA cycle suppression also engenders an apparently homeostatic accelerated, inefficient consumption of nutrient stores in carcinoma cells, eroding some sources of drug resistance. Nonetheless, sufficiently abundant, cell line-specific lipid stores in carcinoma cells are among remaining sources of CPI-613 resistance in vitro and during the in vivo pharmacological drug pulse. Specifically, the fatty acid beta-oxidation step delivers electrons directly to the mitochondrial electron transport system (ETC), by-passing the TCA cycle CPI-613 target and producing drug resistance. Strikingly, tested carcinoma cell lines configure much of this fatty acid flow to initially traverse the peroxisome enroute to additional mitochondrial beta-oxidation. This feature facilitates targeting as clinically practical agents disrupting this flow are available. Two such agents significantly sensitize an otherwise fully CPI-613-resistant carcinoma xenograft in vivo. These and related results are strong empirical support for a potentially general class of strategies for enhanced clinical targeting of carcinoma catabolism.
    DOI:  https://doi.org/10.1371/journal.pone.0269620
  8. Front Oncol. 2022 ;12 863329
    The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression.
    Lin Xiao, Mawar Karsa, Emma Ronca, Angelika Bongers, Angelika Kosciolek, Ali El-Ayoubi, Jezrael L Revalde, Janith A Seneviratne, Belamy B Cheung, Laurence C Cheung, Rishi S Kotecha, Andrea Newbold, Stefan Bjelosevic, Greg M Arndt, Richard B Lock, Ricky W Johnstone, Andrei V Gudkov, Katerina V Gurova, Michelle Haber, Murray D Norris, Michelle J Henderson, Klaartje Somers.
      Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 (KMT2A:MLLT3) driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on KMT2A rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.
    Keywords:  KMT2A-rearranged leukemia; chromatin; curaxin CBL0137; histone deacetylase inhibition; infant leukemia
    DOI:  https://doi.org/10.3389/fonc.2022.863329
  9. Nat Cell Biol. 2022 Jun 06.
    The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness.
    Geethu Emily Thomas, Grace Egan, Laura García-Prat, Aaron Botham, Veronique Voisin, Parasvi S Patel, Fieke W Hoff, Jordan Chin, Boaz Nachmias, Kerstin B Kaufmann, Dilshad H Khan, Rose Hurren, Xiaoming Wang, Marcela Gronda, Neil MacLean, Cristiana O'Brien, Rashim P Singh, Courtney L Jones, Shane M Harding, Brian Raught, Andrea Arruda, Mark D Minden, Gary D Bader, Razq Hakem, Steve Kornblau, John E Dick, Aaron D Schimmer.
      Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function.
    DOI:  https://doi.org/10.1038/s41556-022-00925-9
  10. Curr Stem Cell Res Ther. 2022 Jun 08.
    cancer cell de-differentiation: plasticity- driven stratagem for tumor metastasis and recurrence.
    E L Mdarsafy Sanaa.
      Tumor recurrence is a colossal challenge in clinical oncology. This multifactorial prob-lem is attributed to the emergence of additional genetic mutations and the presence of dormant cancer cells. However, plasticity of non-stem cancer cells and the acquisi-tion of cancer stem cell (CSC) functionality is another contributing factor for tumor recurrence. Herein, I focus attention on the mechanisms that fuel cancer cell de-differentiation and the interplay between intra-cellular regulators and tumor micro-environment (TME) landscape that promote cancer cell stemness. Our understanding of the mechanisms underlying tumor cell de-differentiation is crucial for developing innovated therapeutic strategies that prevent cancer from ever recuring.
    Keywords:  Cancer cell dormancy; Cancer cell immune evasion; Cancer cell plasticity; Cancer stem cells; De-differentiation; Epithelial- mesenchymal transition
    DOI:  https://doi.org/10.2174/1574888X17666220608101852
  11. Colloids Surf B Biointerfaces. 2022 Jun 01. pii: S0927-7765(22)00292-2. [Epub ahead of print]217 112609
    Novel nanocarriers for silencing anti-phagocytosis CD47 marker in acute myeloid leukemia cells.
    Eman M Hassan, Shan Zou.
      Acute myeloid leukemia (AML), a malignant disorder of Hematopoietic stem cells, can escape immunosurveillance by over expression of the cluster of differentiation 47 (CD47) marker, which functions as an inhibitory signal, suppressing phagocytosis by binding to signal regulatory protein α (SIRPα) on macrophages. AML is treated mainly by chemotherapy, which has drastic side effects and poor outcomes for the patients. Most AML patients develop drug resistance, so other methods to treat AML are highly required. Small interfering RNA (siRNA) is considered as an antitumor therapeutic due to its ability to silence genes associated with the overexpressed cancer markers and subsequently re-sensitize cancer cells. However, delivering siRNA into cells faces challenges, and the development of an effective delivery system is desired for successful silencing at the gene level. Herein, we report the usage of different formulations of graphene oxide (GO) as carriers for the delivery of CD47_siRNA (siRNA against CD47) into AML cells in vitro. The polyethylene glycol (PEG) and dendrimers (PAMAM) modified GO with small flake sizes achieved the highest silencing efficiency of the anti-phagocytosis marker CD47 gene, resulted CD47 protein down-regulation in AML cells. Moreover, the concentration at which the GO-based formulations was used has shown no cytotoxicity in AML cells or normal blood cells, which could be used to screen potential drugs for targeted gene therapy in AML.
    Keywords:  Graphene oxide (GO); Nano-conjugate; Small interfering RNA (siRNA); Surface modification; knockdown efficiency
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112609
  12. Cell Rep. 2022 Jun 07. pii: S2211-1247(22)00689-1. [Epub ahead of print]39(10): 110912
    Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle.
    Sophia Urbanczyk, Olivier R Baris, Jörg Hofmann, R Verena Taudte, Naïg Guegen, Florian Golombek, Kathrin Castiglione, Xianyi Meng, Aline Bozec, Jana Thomas, Leonie Weckwerth, Dimitrios Mougiakakos, Sebastian R Schulz, Wolfgang Schuh, Ursula Schlötzer-Schrehardt, Tobit D Steinmetz, Susanne Brodesser, Rudolf J Wiesner, Dirk Mielenz.
      To elucidate the function of oxidative phosphorylation (OxPhos) during B cell differentiation, we employ CD23Cre-driven expression of the dominant-negative K320E mutant of the mitochondrial helicase Twinkle (DNT). DNT-expression depletes mitochondrial DNA during B cell maturation, reduces the abundance of respiratory chain protein subunits encoded by mitochondrial DNA, and, consequently, respiratory chain super-complexes in activated B cells. Whereas B cell development in DNT mice is normal, B cell proliferation, germinal centers, class switch to IgG, plasma cell maturation, and T cell-dependent as well as T cell-independent humoral immunity are diminished. DNT expression dampens OxPhos but increases glycolysis in lipopolysaccharide and B cell receptor-activated cells. Lipopolysaccharide-activated DNT-B cells exhibit altered metabolites of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle and a lower amount of phosphatidic acid. Consequently, mTORC1 activity and BLIMP1 induction are curtailed, whereas HIF1α is stabilized. Hence, mitochondrial DNA controls the metabolism of activated B cells via OxPhos to foster humoral immunity.
    Keywords:  B lymphocyte; CP: Immunology; HIF1; TCA cycle; class switch recombination; germinal center; hypoxia inducible factor 1; mTOR; mammalian target of Rapamycin; mitochondrial DNA; mitochondrial respiration; oxidative phosphorylation; phosphatidic acid; plasma cell
    DOI:  https://doi.org/10.1016/j.celrep.2022.110912
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