bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–10–31
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Mitochondrial Effects on Seeds of Cancer Survival in Leukemia.
  2. Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow.
  3. Targeting mitochondrial metabolism in acute myeloid leukemia.
  4. Active mitochondrial respiration in cancer: a target for the drug.
  5. PLCG1 is required for AML1-ETO leukemia stem cell self-renewal.
  6. CD157 signaling promotes survival of acute myeloid leukemia cells and modulates sensitivity to cytarabine through regulation of anti-apoptotic Mcl-1.
  7. Editorial: Metabolic Rewiring in Leukemias.
  8. CD200 expression in hematopoietic neoplasms: beyond a marker for diagnosis of B-cell neoplasms.
  1. Front Oncol. 2021 ;11 745924
    Mitochondrial Effects on Seeds of Cancer Survival in Leukemia.
    Hend E El-Shaqanqery, Rania Hassan Mohamed, Ahmed A Sayed.
      The cancer metabolic alteration is considered a hallmark and fast becoming a road for therapeutic intervention. Mitochondria have been regarded as essential cell elements that fuel the metabolic needs of most cancer cell types. Leukemia stem cells (LSCs) are a heterogeneous, highly self-renewing, and pluripotent cell population within leukemic cells. The most important source of ATP and metabolites to fulfill the bioenergetics and biosynthetic needs of most cancer stem cells is the mitochondria. In addition, mitochondria have a core role in autophagy and cell death and are the main source of reactive oxygen species (ROS) generation. Overall, growing evidence now shows that mitochondrial activities and pathways have changed to adapt with different types of leukemia, thus mitochondrial metabolism could be targeted for blood malignancy therapy. This review focuses on the function of mitochondria in LSC of the different leukemia types.
    Keywords:  leukemia; leukemia stem cell; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fonc.2021.745924
  2. J Histochem Cytochem. 2021 Oct 29. 221554211054585
    Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow.
    Cornelis J F van Noorden, Barbara Breznik, Metka Novak, Amber J van Dijck, Saloua Tanan, Miloš Vittori, Urban Bogataj, Noëlle Bakker, Joseph D Khoury, Remco J Molenaar, Vashendriya V V Hira.
      Energy production by means of ATP synthesis in cancer cells has been investigated frequently as a potential therapeutic target in this century. Both (an)aerobic glycolysis and oxidative phosphorylation (OXPHOS) have been studied. Here, we review recent literature on energy production in glioblastoma stem cells (GSCs) and leukemic stem cells (LSCs) versus their normal counterparts, neural stem cells (NSCs) and hematopoietic stem cells (HSCs), respectively. These two cancer stem cell types were compared because their niches in glioblastoma tumors and in bone marrow are similar. In this study, it became apparent that (1) ATP is produced in NSCs and HSCs by anaerobic glycolysis, whereas fatty acid oxidation (FAO) is essential for their stem cell fate and (2) ATP is produced in GSCs and LSCs by OXPHOS despite the hypoxic conditions in their niches with FAO and amino acids providing its substrate. These metabolic processes appeared to be under tight control of cellular regulation mechanisms which are discussed in depth. However, our conclusion is that systemic therapeutic targeting of ATP production via glycolysis or OXPHOS is not an attractive option because of its unwanted side effects in cancer patients.
    Keywords:  angiogenesis; bone marrow; brain tumors; cancer stem cells; hematopoietic stem cells; leukemia; leukemic stem cells; metabolism; neural stem cells; niches; stem cells; stemness; tumor heterogeneity; tumor immune infiltrate; tumor microenvironment
    DOI:  https://doi.org/10.1369/00221554211054585
  3. Leuk Lymphoma. 2021 Oct 27. 1-8
    Targeting mitochondrial metabolism in acute myeloid leukemia.
    Madison Rush Rex, Robert Williams, Kivanç Birsoy, Martin S Ta Llman, Maximillian Stahl.
      Cancer cells reprogram their metabolism to maintain sustained proliferation, which creates unique metabolic dependencies between malignant and healthy cells that can be exploited for therapy. In acute myeloid leukemia (AML), mitochondrial inhibitors that block tricarboxylic acid cycle enzymes or electron transport chain complexes have recently shown clinical promise. The isocitrate dehydrogenase 1 inhibitor ivosidenib, the isocitrate dehydrogenase 2 inhibitor enasidenib, and the BH3 mimetic venetoclax received FDA approval for treatment of AML in the last few years. Other mitochondrial inhibitors including CPI-613, CB-839, dihydroorotate dehydrogenase inhibitors, IACS-010759, and mubritinib, have shown encouraging preclinical efficacy and are currently being evaluated in clinical trials. In this review, we summarize recent metabolism-based therapies and their ability to target altered cancer metabolism in AML.
    Keywords:  Targeted therapy; acute myeloid leukemia; mitochondrial metabolism
    DOI:  https://doi.org/10.1080/10428194.2021.1992759
  4. Mol Cell Biochem. 2021 Oct 30.
    Active mitochondrial respiration in cancer: a target for the drug.
    Minakshi Bedi, Manju Ray, Alok Ghosh.
      The relative contribution of mitochondrial respiration and subsequent energy production in malignant cells has remained controversial to date. Enhanced aerobic glycolysis and impaired mitochondrial respiration have gained more attention in the metabolic study of cancer. In contrast to the popular concept, mitochondria of cancer cells oxidize a diverse array of metabolic fuels to generate a majority of the cellular energy by respiration. Several mitochondrial respiratory chain (MRC) subunits' expressions are critical for the growth, metastasis, and cancer cell invasion. Also, the assembly factors, which regulate the integration of individual MRC complexes into native super-complexes, are upregulated in cancer. Moreover, a series of anti-cancer drugs function by inhibiting respiration and ATP production. In this review, we have specified the roles of mitochondrial fuels, MRC subunits, and super-complex assembly factors that promote active respiration across different cancer types and discussed the potential roles of MRC inhibitor drugs in controlling cancer.
    Keywords:  Cancer; Drugs; Metabolic fuels; Mitochondria; Respiratory chain subunits; Super-complex
    DOI:  https://doi.org/10.1007/s11010-021-04281-4
  5. Blood. 2021 Oct 25. pii: blood.2021012778. [Epub ahead of print]
    PLCG1 is required for AML1-ETO leukemia stem cell self-renewal.
    Tina M Schnoeder, Adrian Schwarzer, Ashok Kumar Jayavelu, Chen-Jen Hsu, Joanna Kirkpatrick, Konstanze Döhner, Florian Perner, Theresa Eifert, Nicolas Huber, Patricia Arreba-Tutusaus, Anna Dolnik, Salam A Assi, Monica Nafria, Lu Jiang, Yu-Ting Dai, Zhu Chen, Sai-Juan Chen, Sophie G Kellaway, Anetta Ptasinska, Elizabeth S Ng, Edouard G Stanley, Andrew G Elefanty, Marcus Buschbeck, Holger Bierhoff, Steffen Brodt, Georg Matziolis, Klaus-Dieter Fischer, Andreas Hochhaus, Chun-Wei Chen, Olaf Heidenreich, Matthias Mann, Steven W Lane, Lars Bullinger, Alessandro Ori, Björn von Eyss, Constanze Bonifer, Florian Heidel.
      In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a de-regulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.
    DOI:  https://doi.org/10.1182/blood.2021012778
  6. Sci Rep. 2021 Oct 27. 11(1): 21230
    CD157 signaling promotes survival of acute myeloid leukemia cells and modulates sensitivity to cytarabine through regulation of anti-apoptotic Mcl-1.
    Yuliya Yakymiv, Stefania Augeri, Cristiano Bracci, Sara Marchisio, Semra Aydin, Stefano D'Ardia, Massimo Massaia, Enza Ferrero, Erika Ortolan, Ada Funaro.
      CD157/BST-1 (a member of the ADP-ribosyl cyclase family) is expressed at variable levels in 97% of patients with acute myeloid leukemia (AML), and is currently under investigation as a target for antibody-based immunotherapy. We used peripheral blood and bone marrow samples from patients with AML to analyse the impact of CD157-directed antibodies in AML survival and in response to cytarabine (AraC) ex vivo. The study was extended to the U937, THP1 and OCI-AML3 AML cell lines of which we engineered CD157-low versions by shRNA knockdown. CD157-targeting antibodies enhanced survival, decreased apoptosis and reduced AraC toxicity in AML blasts and cell lines. CD157 signaling activated the PI3K/AKT/mTOR and MAPK/ERK pathways and increased expression of Mcl-1 and Bcl-XL anti-apoptotic proteins, while decreasing expression of Bax pro-apoptotic protein, thus preventing Caspase-3 activation. The primary CD157-mediated anti-apoptotic mechanism was Bak sequestration by Mcl-1. Indeed, the Mcl-1-specific inhibitor S63845 restored apoptosis by disrupting the interaction of Mcl-1 with Bim and Bak and significantly increased AraC toxicity in CD157-high but not in CD157-low AML cells. This study provides a new role for CD157 in AML cell survival, and indicates a potential role of CD157 as a predictive marker of response to therapies exploiting Mcl-1 pharmacological inhibition.
    DOI:  https://doi.org/10.1038/s41598-021-00733-5
  7. Front Oncol. 2021 ;11 775167
    Editorial: Metabolic Rewiring in Leukemias.
    Nelida I Noguera, Syed K Hasan, Emanuele Ammatuna, Adriano Venditti.
      
    Keywords:  ALL and adipocytes; ROS; chemoresistance; dihydroorotate dehydrogenase (DHODH); ketone body metabolism; leukemia; metabolic plasticity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.775167
  8. Crit Rev Oncol Hematol. 2021 Oct 21. pii: S1040-8428(21)00296-1. [Epub ahead of print] 103509
    CD200 expression in hematopoietic neoplasms: beyond a marker for diagnosis of B-cell neoplasms.
    Renata B Staub, Natália A Marcondes, Liane N Rotta.
      CD200 (OX-2) is expressed in myeloid cells, B cells, subsets of T cells and on other normal and neoplastic non-hematopoietic cells. It interacts with CD200R and has a suppressive effect on T cells immune mediated response. We aimed to review CD200 expression and its role in the immune evasion of non-B cell hematopoietic neoplasms. In acute myeloid leukemia, CD200 seems to be related to the worst outcome, even in diseases of good prognosis, possibly due to an immunosuppressive effect. In plasma cell myeloma studies, while some have associated CD200 expression with worst prognosis possibly due to its suppressive effect on monocyte and T cell-mediated immune response, in others CD200 appeared to be a marker of a better outcome, or even showed no impact in event-free survival (EFS). Few studies have evaluated CD200 expression in T cell neoplasms; however, it appears to be a good immunophenotypic marker for angioimmunoblastic T cell lymphoma. In conclusion, CD200 appears to be involved in the immune evasion of malignant cells, which could affect the survival of these patients.
    Keywords:  CD200; OX-2; hematopoietic neoplasms; immune response
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103509
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