bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022‒01‒16
fifteen papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Non-oncogene Addiction to SIRT5 in Acute Myeloid Leukemia.
  2. Cancer non-stem cells as a potent regulator of tumor microenvironment: a lesson from chronic myeloid leukemia.
  3. Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia.
  4. Amino Acid Metabolism in Cancer Drug Resistance.
  5. Cancer metabolism and intervention therapy.
  6. Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism.
  7. A Novel Function of Sphingolipid Signaling via S1PR3 in Hematopoietic and Leukemic Stem Cells.
  8. What Happens to the Immune Microenvironment After PD-1 Inhibitor Therapy?
  9. Copper modulates heart mitochondrial H2O2 emission differently during fatty acid and pyruvate oxidation.
  10. Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives.
  11. Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.
  12. Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia.
  13. Remodeling metabolic fitness: Strategies for improving the efficacy of chimeric antigen receptor T cell therapy.
  14. Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations.
  15. Proteomics: a new era in pediatric acute myeloid leukemia research.
  1. Blood Cancer Discov. 2021 May;2(3): 198-200
    Non-oncogene Addiction to SIRT5 in Acute Myeloid Leukemia.
    Meng Li, Ari M Melnick.
      In this issue of Blood Cancer Discovery, Yan and colleagues discovered that mitochondrial deacylase, SIRT5, is required in AML cells to support mitochondrial oxidative phosphorylation, maintain redox homeostasis, and drive glutaminolysis. The new SIRT5 inhibitor, NRD167, can efficiently target SIRT5 in AMLs at micromolar range and may constitute a novel therapeutic approach to improve clinical outcomes of patients with AML.See related article by Yan et al., p. 266.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0026
  2. Mol Biomed. 2021 Mar 10. 2(1): 7
    Cancer non-stem cells as a potent regulator of tumor microenvironment: a lesson from chronic myeloid leukemia.
    Naofumi Mukaida, Yamato Tanabe, Tomohisa Baba.
      A limited subset of human leukemia cells has a self-renewal capacity and can propagate leukemia upon their transplantation into animals, and therefore, are named as leukemia stem cells, in the early 1990's. Subsequently, cell subpopulations with similar characteristics were detected in various kinds of solid cancers and were denoted as cancer stem cells. Cancer stem cells are presently presumed to be crucially involved in malignant progression of solid cancer: chemoresitance, radioresistance, immune evasion, and metastasis. On the contrary, less attention has been paid to cancer non-stem cell population, which comprise most cancer cells in cancer tissues, due to the lack of suitable markers to discriminate cancer non-stem cells from cancer stem cells. Chronic myeloid leukemia stem cells generate a larger number of morphologically distinct non-stem cells. Moreover, accumulating evidence indicates that poor prognosis is associated with the increases in these non-stem cells including basophils and megakaryocytes. We will discuss the potential roles of cancer non-stem cells in fostering tumor microenvironment, by illustrating the roles of chronic myeloid leukemia non-stem cells including basophils and megakaryocytes in the pathogenesis of chronic myeloid leukemia, a typical malignant disorder arising from leukemic stem cells.
    Keywords:  Basophil; Cancer stem cell; Leukemia stem cell; Megakaryocyte; Tissue-resident stem cell
    DOI:  https://doi.org/10.1186/s43556-021-00030-7
  3. Mol Biol Rep. 2022 Jan 14.
    Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia.
    Garrett M Dancik, Ioannis F Voutsas, Spiros Vlahopoulos.
      The expression and activity of enzymes that belong to the aldehyde dehydrogenases is a characteristic of both normal and malignant stem cells. ALDH1A1 is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemia-initiating cells from a number of antineoplastic agents, which include inhibitors of protein tyrosine kinases. Furthermore, ALDH1A1 proves vital for the establishment of human AML xenografts in mice. We review here important studies characterizing the role of ALDH1A1 in AML and its potential as a therapeutic target. We also analyze datasets from leading studies, and show that decreased ALDH1A1 RNA expression consistently characterizes the AML patient risk group with a favorable prognosis, while there is a consistent association of high ALDH1A1 RNA expression with high risk and poor overall survival. Our review and analysis reinforces the notion to employ both novel as well as existing inhibitors of the ALDH1A1 protein against AML.
    Keywords:  Aldehyde dehydrogenase; Biomarkers; Drug resistance; Gene expression; Immunosuppression; Leukemia, myeloid, acute; Neoplastic Stem cells
    DOI:  https://doi.org/10.1007/s11033-021-07073-7
  4. Cells. 2022 Jan 02. pii: 140. [Epub ahead of print]11(1):
    Amino Acid Metabolism in Cancer Drug Resistance.
    Hee-Chan Yoo, Jung-Min Han.
      Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.
    Keywords:  amino acids; cancer; drug resistance; immune response
    DOI:  https://doi.org/10.3390/cells11010140
  5. Mol Biomed. 2021 Feb 20. 2(1): 5
    Cancer metabolism and intervention therapy.
    Huakan Zhao, Yongsheng Li.
      Metabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.
    Keywords:  Cancer; Heterogeneity; Metabolic reprogramming; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s43556-020-00012-1
  6. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4188-4197
    Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism.
    Vijayalakshmi Amash, Khanderao Paithankar, Shrikant Purushottam Dharaskar, Abirami Arunachalam, Sreedhar Amere Subbarao.
      Among human diseases, cancer has been in the frontlines of drug discovery and development. Despite having several decades of research efforts, therapeutic targeting of cancer is still challenging, which is due to the ability of cancer cells to adapt to the tumor microenvironment, exhibiting resistance to therapeutic drugs, and facilitated altered cancer metabolism. The small molecule inhibitors aimed at targeting a selective pathway are becoming void since cancer cells can activate alternate mechanisms. Despite broad acceptance of the Warburg effect, cellular energy metabolism, which determines the cell fate, is often overlooked for cancer treatment. We reported earlier that mitochondrial chaperone, TRAP-1 acts as a switch for activating the alternate cellular metabolism. Hence, we hypothesized that interfering with TRAP-1 inhibition can target the activation of alternative energy metabolism and sensitize tumor cells to existing chemotherapeutic drugs. We developed a nanocarrier where the iron oxide nanoparticles (IONs) were conjugated to Hsp90 inhibitor, geldanamycin (GA), and the mitochondria localization signal (MLS) peptide. We examined its effect against mitochondrial dynamics and metabolic status of human tumor cells. The synthesized nanocarrier exhibited both stability and target-specific activity and did not show nanoparticle-associated cytotoxicity. However, the nanocarrier treated cancer cells exhibited altered mitochondrial morphology and decreased cellular ATP levels suggesting that selective TRAP-1 targeting interferes with the altered energy metabolism. We present a nanoparticle-based TRAP-1 inhibitor to target tumor metabolism.
    Keywords:  MLS peptide; TRAP-1; cancer; geldanamycin; iron oxide nanoparticles; mitochondrion
    DOI:  https://doi.org/10.1021/acsabm.0c00268
  7. Blood Cancer Discov. 2021 Jan;2(1): 3-5
    A Novel Function of Sphingolipid Signaling via S1PR3 in Hematopoietic and Leukemic Stem Cells.
    Chong Yang, Masayuki Yamashita, Toshio Suda.
      In this issue of Blood Cancer Discovery, Xie and colleagues describe a novel function of sphingosine-1-phosphate receptor 3 (S1PR3) to regulate myeloid differentiation and activate inflammatory programs in both human hematopoietic stem cells and leukemic stem cells. They propose S1PR3 as a major downstream signaling pathway of a TNFα-NF-κB axis in this study and unlock potential therapeutic opportunities to improve outcomes of patients with acute myeloid leukemia by modulating sphingolipid signaling via S1PR3.See related article by Xie et al., p. 32.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0200
  8. Front Immunol. 2021 ;12 773168
    What Happens to the Immune Microenvironment After PD-1 Inhibitor Therapy?
    Qingyi Wang, Bin Xie, Shuang Liu, Ying Shi, Yongguang Tao, Desheng Xiao, Wenxiang Wang.
      The fruitful results of tumor immunotherapy establish its indispensable status in the regulation of the tumorous immune context. It seems that the treatment of programmed cell death receptor 1 (PD-1) blockade is one of the most promising approaches for cancer control. The significant efficacy of PD-1 inhibitor therapy has been made in several cancer types, such as breast cancer, lung cancer, and multiple myeloma. Even so, the mechanisms of how anti-PD-1 therapy takes effect by impacting the immune microenvironment and how partial patients acquire the resistance to PD-1 blockade have yet to be studied. In this review, we discuss the cross talk between immune cells and how they promote PD-1 blockade efficacy. In addition, we also depict factors that may underlie tumor resistance to PD-1 blockade and feasible solutions in combination with it.
    Keywords:  PD-1 inhibitor; combined immunotherapy; cytotoxic T lymphocytes (CTLs); immunotherapy; immunotherapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.773168
  9. Comp Biochem Physiol C Toxicol Pharmacol. 2022 Jan 10. pii: S1532-0456(22)00002-3. [Epub ahead of print] 109267
    Copper modulates heart mitochondrial H2O2 emission differently during fatty acid and pyruvate oxidation.
    Michael O Isei, Don Stevens, Collins Kamunde.
      Although the preferred cardiac metabolic fuels are fatty acids, glucose metabolism also plays an important role. However, irrespective of substrate type, energy generation results in mitochondrial reactive oxygen species (ROS) formation. To determine if the preference of fat over carbohydrates predisposes cardiomyocytes to oxidant production, we measured total and site-specific H2O2 emission in heart mitochondria oxidizing palmitoylcarnitine or pyruvate during copper (Cu) exposure. H2O2 emission was higher during oxidation of palmitoylcarnitine compared with pyruvate. Moreover, the bulk of the H2O2 emitted during palmitoylcarnitine oxidation originated from the outer ubiquinone binding site of complex III (site IIIQo) and the flavin site of electron transfer flavoprotein (site EF). We found no evidence of ROS production from complex I ubiquinone-binding site (site IQ) by reverse electron transport during oxidation of palmitoylcarnitine. Pyruvate oxidation also drove H2O2 emission primarily from sites IIIQo; however, the flavin sites of pyruvate dehydrogenase (site PF) and complex II (site IIF) contributed substantially. The effect of Cu depended on substrate and redox site, with effects at sites OF and IIIQo being more pronounced in mitochondria oxidizing pyruvate compared with palmitoylcarnitine. Cu imposed a concentration-saturable effect at site PF but concentration-dependently stimulated H2O2 emission at site EF. The substrate-dependent differences in H2O2 emission and effects of Cu suggest that fuel type and points of entry of electrons into the mitochondrial electron transport system determine the mitochondrial ROS production rate. Importantly, knowledge of sites of mitochondrial ROS production is crucial to the understanding of cardiac dysfunction associated with impaired substrate metabolism.
    Keywords:  Copper; Fish; Heart mitochondria; Metabolic substrate preference; Total and site-specific ROS production
    DOI:  https://doi.org/10.1016/j.cbpc.2022.109267
  10. Cancers (Basel). 2022 Jan 04. pii: 245. [Epub ahead of print]14(1):
    Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives.
    Ruggiero Gorgoglione, Valeria Impedovo, Christopher L Riley, Deborah Fratantonio, Stefano Tiziani, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.
      Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.
    Keywords:  SLC1A5_var; UCP2; aspartate; aspartate/glutamate carrier; cancer; glutamate carrier; glutamine metabolism; mitochondrial carriers
    DOI:  https://doi.org/10.3390/cancers14010245
  11. Cancers (Basel). 2021 Dec 29. pii: 150. [Epub ahead of print]14(1):
    Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.
    Amber Gibson, Adriana Trabal, David McCall, Sajad Khazal, Laurie Toepfer, Donna H Bell, Michael Roth, Kris M Mahadeo, Cesar Nunez, Nicholas J Short, Courtney DiNardo, Marina Konopleva, Ghayas C Issa, Farhad Ravandi, Nitin Jain, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Branko Cuglievan.
      Venetoclax is approved for adult patients with chronic lymphocytic leukemia and acute myeloid leukemia. Expanding its use to the pediatric population is currently under investigation, but more robust data are needed. We retrospectively analyzed the safety and efficacy of venetoclax in children/AYA with ALL/LBL. We identified 18 patients (T-cell ALL, n = 7; T-cell LBL, n = 6; B-cell ALL, n = 5) aged 6-22 years. No new venetoclax safety signals were identified; the most common toxicity was myelosuppression. No deaths occurred within 30 days from the start of the therapy. A mean of 2.6 (range 0-8) prior lines of therapy were given. The mean duration of venetoclax was 4.06 months (range 0.2-24.67 months). Complete remission was achieved in 11 (61%) patients. Of the eight patients who remain alive, four are continuing on venetoclax combination therapy, and four proceeded to hematopoietic stem cell transplantation. Three patients who initially achieved CR, later relapsed, and are deceased. Nine patients are deceased, and one patient was lost to follow-up. Overall survival is 9.14 months (range 1.1-33.1), and progression-free survival is 7.34 months (range 0.2-33.1). This is the largest cohort of pediatric/AYA patients who received venetoclax for ALL/LBL. Our data support the consideration of venetoclax-based regimens in pediatric patients with R/R ALL/LBL and its investigation as upfront therapy for T-cell ALL/LBL.
    Keywords:  Bcl-2 inhibitor; acute lymphoblastic leukemia; early precursor T-cell; lymphoblastic lymphoma; venetoclax
    DOI:  https://doi.org/10.3390/cancers14010150
  12. Cancers (Basel). 2021 Dec 27. pii: 105. [Epub ahead of print]14(1):
    Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia.
    Matthias Böhme, Sabine Kayser.
      The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data.
    Keywords:  T-cell immune checkpoint inhibitors; acute myeloid leukemia; bispecific and dual antigen receptor-targeting antibodies; chimeric antigen receptor T-cell therapies; immunotherapy
    DOI:  https://doi.org/10.3390/cancers14010105
  13. Cancer Lett. 2022 Jan 07. pii: S0304-3835(22)00006-4. [Epub ahead of print]529 139-152
    Remodeling metabolic fitness: Strategies for improving the efficacy of chimeric antigen receptor T cell therapy.
    Luyan Shen, Yefei Xiao, Jiahe Tian, Zheming Lu.
      The dramatic success of adoptive transfer of engineered T cells expressing chimeric antigen receptor (CAR-T) has been achieved with effective responses in some relapsed or refractory hematologic malignancies, which is not yet met in solid tumors. The efficacy of CAR-T therapy is associated with its fate determination and their interaction with cancer cells in tumor microenvironment (TME), which is closely correlated with T cell metabolism fitness. Indeed, modulating T cell metabolism reprogramming has been proven crucial for their survival and reinvigorating antitumor immunity, and thus is considered as a promising strategy to improve the clinical performance of CAR-T cell therapy in difficult-to-treat cancers. This review briefly summarizes the T cell metabolic profiles and key metabolic challenges it faces in TME such as nutrient depletion, hypoxia, and toxic metabolites, then emphatically discusses the potential strategies to modulate metabolic properties of CAR-T cells including improving CARs construct design, optimizing manufacture process via addition of exogenous cytokines or targeting specific signaling pathway, manipulating ROS levels balance or relieving the unfavorable metabolic TME including adaptation to hypoxia and blocking inhibitory effect of toxic metabolites, eventually strengthening the anti-tumor response.
    Keywords:  Glycolysis; Hypoxia; Immunosuppressive TME; Mitochondrial OXPHOS; T cell differentiation
    DOI:  https://doi.org/10.1016/j.canlet.2022.01.006
  14. Cell Rep Med. 2021 Dec 21. 2(12): 100469
    Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations.
    Ingvild Comfort Hvinden, Tom Cadoux-Hudson, Christopher J Schofield, James S O McCullagh.
      The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since IDH mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in IDH lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to R-2-hydroxyglutarate (R-2-HG). It is proposed that elevated cellular R-2-HG inhibits enzymes that regulate transcription and metabolism, subsequently affecting nuclear, cytoplasmic, and mitochondrial biochemistry. The significance of these biochemical changes for tumorigenesis and potential for therapeutic exploitation remains unclear. Here we comprehensively review reported direct and indirect metabolic changes linked to IDH mutations and discuss their clinical significance. We also review the metabolic effects of first-generation mutant IDH inhibitors and highlight the potential for combination treatment strategies and new metabolic targets.
    Keywords:  2-oxoglutarate; IDH inhibition; R-2-HG; R-2-hydoxyglutarate; TCA cycle; cancer metabolism; chromatin modification; histone modification; metabolic target; mutant isocitrate dehydrogenase; redox metabolism
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100469
  15. Haematologica. 2022 Jan 13.
    Proteomics: a new era in pediatric acute myeloid leukemia research.
    Jatinder K Lamba, Stanley Pounds.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2021.280305
This page is being maintained by Thomas Krichel. It was last updated on 2022‒01‒16 at 19:57:37.