bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021‒09‒12
twenty papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Future perspective: metabolism as a therapeutic target in acute myeloid leukemia - from Warburg to precision medicine.
  2. T cells critically depend on pyruvate oxidation.
  3. Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
  4. Stem Cells in Myelodysplastic Syndromes and Acute Myeloid Leukemia: First Cousins or Unrelated Entities?
  5. The Combined Treatment With the FLT3-Inhibitor AC220 and the Complex I Inhibitor IACS-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells.
  6. Glutamine promotes escape from therapy-induced senescence in tumor cells.
  7. The nexus between redox state and intermediary metabolism.
  8. More Than Meets the Eye Regarding Cancer Metabolism.
  9. Genomic instability and metabolism in cancer.
  10. SMPDL3B Predicts Poor Prognosis and Contributes to Development of Acute Myeloid Leukemia.
  11. Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using cross-over dual-variable domain (CODV) format for acute myeloid leukemia (AML) treatment.
  12. New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway.
  13. PPARα at the Crossroad of Metabolic-Immune Regulation in Cancer.
  14. Pharmacological effects on anaplerotic pathways alters the metabolic landscape in the tumor microenvironment, causing unpredictable, sustained antitumor immunity.
  15. Guiding immunotherapy combinations: who gets what?
  16. Epigenetic Therapy Promotes the Ratio of Th1/Th17 Lineage to Reverse Immune Evasion and Treat Leukemia Relapse Post-allogeneic Stem Cell Transplantation in Non-APL AML Patients.
  17. The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance.
  18. DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis.
  19. Role of Copper on Mitochondrial Function and Metabolism.
  20. Loss of the redox mitochondrial protein mitoNEET leads to mitochondrial dysfunction in B-cell acute lymphoblastic leukemia.
  1. Curr Med Res Opin. 2021 Sep 09. 1
    Future perspective: metabolism as a therapeutic target in acute myeloid leukemia - from Warburg to precision medicine.
    Kimberley Joanne Hatfield, Ida Sofie Grønningsaeter, Håkon Reikvam.
      Acute myeloid leukemia (AML) is a highly malignant blood cancer disease, with dismal prognosis. The theory that cancer cells utilize metabolism to their growth advantage was postulated almost hundred years ago. However, only recently have been able to take advantage of this Achilles heel of malignant cell growth. Current observations suggest a crucial role for various metabolic pathways in AML, and special in leukemia stem cells (LSC), believed to be responsible for re-initiation of the leukemic clone, and hence relapse of this devastating disease. In the present article we discuss the features for metabolism in AML based on recent research, and special emphasizing the potential of pharmacological inhibiting metabolism as new treatment approaches.
    Keywords:  Acute myelogenous leukemia – Leukemia stem cells – Metabolism – Signaling pathways – Targeted therapy
    DOI:  https://doi.org/10.1080/03007995.2021.1978960
  2. Cell Metab. 2021 Sep 07. pii: S1550-4131(21)00373-9. [Epub ahead of print]33(9): 1719-1720
    T cells critically depend on pyruvate oxidation.
    Christopher Schrecker, Andrew M Intlekofer.
      Supporting the notion that cell lineage is a key determinant of cancer cell metabolism, Jun et al. (2021) identify a selective requirement for pyruvate dehydrogenase (PDH) activity in T cells and T cell leukemia, but not hematopoietic stem cells (HSCs) or myeloid leukemia, in this issue of Cell Metabolism.
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.010
  3. Blood Adv. 2021 Sep 10. pii: bloodadvances.2020003661. [Epub ahead of print]
    Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
    Kaori Saito, Qi Zhang, Haeun Yang, Kotoko Yamatani, Tomohiko Ai, Vivian Ruvolo, Natalia Baran, Tianyu Cai, Helen Ma, Rodrigo Jacamo, Vinitha Mary Kuruvilla, Junichi Imoto, Sonoko Kinjo, Kazuho Ikeo, Kaori Moriya, Koya Suzuki, Takashi Miida, Yong-Mi Kim, Christopher P Vellano, Michael Andreeff, Joseph R Marszalek, Yoko Tabe, Marina Y Konopleva.
      Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival and continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of mtDNA expression and mitochondrial reactive oxygen species generation, indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, OxPhos inhibition induced (1) transfer of mesenchymal stem cell (MSC)-derived mitochondria to AML cells via tunneling nanotubes under direct-contact coculture conditions, and (2) mitochondrial fission with an increase in functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, and we observed mitochondrial transport to the leading edge of protrusions of migrating AML cells toward MSCs by electron microscopy analysis. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased OxPhos inhibition-triggered mitochondrial transfer from MSCs to AML cells. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003661
  4. Front Oncol. 2021 ;11 730899
    Stem Cells in Myelodysplastic Syndromes and Acute Myeloid Leukemia: First Cousins or Unrelated Entities?
    Romane Joudinaud, Thomas Boyer.
      Myelodysplastic syndromes (MDSs) are associated with a significant risk of transformation to acute myeloid leukemia (AML), supported by alterations affecting malignant stem cells. This review focuses on the metabolic, phenotypic and genetic characteristics underlying this dynamic evolution, from myelodysplastic stem cells (MDS-SCs) to leukemic stem cells (LSCs). MDS-SCs are more likely to be derived from healthy hematopoietic stem cells (HSCs), whereas LSCs may originate from healthy progenitors, mostly LMPP (lymphoid-primed multipotential progenitors). Moreover, overexpression of CD123 and CLL1 markers by LSCs and MDS-SCs in high risk-MDS [HR-MDS] has led to exciting therapeutic applications. Single-cell sequencing has suggested that clonal evolution in the stem cell compartment was non-linear during MDS initiation and progression to AML, with pre-MDS-SC acquiring distinct additional mutations in parallel, that drive either MDS blast production or AML transformation. In AML and HR-MDS, common metabolic alterations have been identified in malignant stem cells, including activation of the protein machinery and dependence on oxidative phosphorylation. Targeting these metabolic abnormalities could prevent HR-MDS from progressing to AML. Strikingly, in low risk-MDS-SC, the expression of ribosomal proteins is decreased, which may be accompanied by a reduction in protein synthesis.
    Keywords:  acute myeloid leukemia; leukemic stem cell; myelodysplastic syndromes; single cell; whole genome sequencing
    DOI:  https://doi.org/10.3389/fonc.2021.730899
  5. Front Oncol. 2021 ;11 686765
    The Combined Treatment With the FLT3-Inhibitor AC220 and the Complex I Inhibitor IACS-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells.
    Xiyuan Lu, Lina Han, Jonathan Busquets, Meghan Collins, Alessia Lodi, Joseph R Marszalek, Marina Konopleva, Stefano Tiziani.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a high mortality rate and relapse risk. Although progress on the genetic and molecular understanding of this disease has been made, the standard of care has changed minimally for the past 40 years and the five-year survival rate remains poor, warranting new treatment strategies. Here, we applied a two-step screening platform consisting of a primary cell viability screening and a secondary metabolomics-based phenotypic screening to find synergistic drug combinations to treat AML. A novel synergy between the oxidative phosphorylation inhibitor IACS-010759 and the FMS-like tyrosine kinase 3 (FLT3) inhibitor AC220 (quizartinib) was discovered in AML and then validated by ATP bioluminescence and apoptosis assays. In-depth stable isotope tracer metabolic flux analysis revealed that IACS-010759 and AC220 synergistically reduced glucose and glutamine enrichment in glycolysis and the TCA cycle, leading to impaired energy production and de novo nucleotide biosynthesis. In summary, we identified a novel drug combination, AC220 and IACS-010759, which synergistically inhibits cell growth in AML cells due to a major disruption of cell metabolism, regardless of FLT3 mutation status.
    Keywords:  FLT3-inhibitor; acute myeloid leukemia; complex I inhibitor; high-throughput screening; metabolomics
    DOI:  https://doi.org/10.3389/fonc.2021.686765
  6. Aging (Albany NY). 2021 Sep 07. 13(undefined):
    Glutamine promotes escape from therapy-induced senescence in tumor cells.
    Francesco Pacifico, Nadia Badolati, Stefano Mellone, Mariano Stornaiuolo, Antonio Leonardi, Elvira Crescenzi.
      Therapy-induced senescence (TIS) is a major cellular response to anticancer therapies. While induction of a persistent growth arrest would be a desirable outcome in cancer therapy, it has been shown that, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, likely contributing to tumor relapse. Notably, cells that escape from TIS acquire a plastic, stem cell-like phenotype. The metabolic dependencies of cells that evade senescence have not been thoroughly studied. In this study, we show that glutamine depletion inhibits escape from TIS in all cell lines studied, and reduces the stem cell subpopulation. In line with a metabolic reliance on glutamine, escaped clones overexpress the glutamine transporter SLC1A5. We also demonstrate a central role of glutamine synthetase that mediates resistance to glutamine deprivation, conferring independence from exogenous glutamine. Finally, rescue experiments demonstrate that glutamine provides nitrogen for nucleotides biosynthesis in cells that escape from TIS, but also suggest a critical involvement of glutamine in other metabolic and non-metabolic pathways. On the whole, these results reveal a metabolic vulnerability of cancer stem cells that recover proliferation after exposure to anticancer therapies, which could be exploited to prevent tumor recurrence.
    Keywords:  cancer stem cells; escape; glutamine; glutamine synthetase; therapy-induced senescence
    DOI:  https://doi.org/10.18632/aging.203495
  7. FEBS J. 2021 Sep 08.
    The nexus between redox state and intermediary metabolism.
    Anna Zoccarato, Adam A Nabeebaccus, Rafael R Oexner, Celio Xc Santos, Ajay M Shah.
      Reactive oxygen species (ROS) are not just a by-product of cellular metabolic processes but act as signalling molecules that regulate both physiological and pathophysiological processes. A close connection exists in cells between redox homeostasis and cellular metabolism. In this review, we describe how intracellular redox state and glycolytic intermediary metabolism are closely coupled. On the one hand, ROS signalling can control glycolytic intermediary metabolism by direct regulation of the activity of key metabolic enzymes and indirect regulation via redox-sensitive transcription factors. On the other hand, metabolic adaptation and reprogramming in response to physiological or pathological stimuli regulate intracellular redox balance, through mechanisms such as the generation of reducing equivalents. We also discuss the impact of these intermediary metabolism-redox circuits in physiological and disease settings across different tissues. A better understanding of the mechanisms regulating these intermediary metabolism-redox circuits will be crucial to the development of novel therapeutic strategies.
    Keywords:  Intermediary metabolism; Redox; Warburg effect; anabolism; reactive oxygen species
    DOI:  https://doi.org/10.1111/febs.16191
  8. Int J Mol Sci. 2021 Sep 01. pii: 9507. [Epub ahead of print]22(17):
    More Than Meets the Eye Regarding Cancer Metabolism.
    Anna Kubicka, Karolina Matczak, Magdalena Łabieniec-Watała.
      In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not "give up" on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation.
    Keywords:  Warburg effect; cancer metabolism; glutamine; glycolysis; lactate; tumour heterogeneity
    DOI:  https://doi.org/10.3390/ijms22179507
  9. Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00063-0. [Epub ahead of print]364 241-265
    Genomic instability and metabolism in cancer.
    Haojian Li, Susan E Zimmerman, Urbain Weyemi.
      Genomic instability and metabolic reprogramming are among the key hallmarks discriminating cancer cells from normal cells. The two phenomena contribute to the robust and evasive nature of cancer, particularly when cancer cells are exposed to chemotherapeutic agents. Genomic instability is defined as the increased frequency of mutations within the genome, while metabolic reprogramming is the alteration of metabolic pathways that cancer cells undergo to adapt to increased bioenergetic demand. An underlying source of these mutations is the aggregate product of damage to the DNA, and a defective repair pathway, both resulting in the expansion of genomic lesions prior to uncontrolled proliferation and survival of cancer cells. Exploitation of DNA damage and the subsequent DNA damage response (DDR) have aided in defining therapeutic approaches in cancer. Studies have demonstrated that targeting metabolic reprograming yields increased sensitivity to chemo- and radiotherapies. In the past decade, it has been shown that these two key features are interrelated. Metabolism impacts DNA damage and DDR via regulation of metabolite pools. Conversely, DDR affects the response of metabolic pathways to therapeutic agents. Because of the interplay between genomic instability and metabolic reprogramming, we have compiled findings which more selectively highlight the dialog between metabolism and DDR, with a particular focus on glucose metabolism and double-strand break (DSB) repair pathways. Decoding this dialog will provide significant clues for developing combination cancer therapies.
    Keywords:  Cancer; DNA repair; Genomic instability; Glycolysis; Metabolism; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/bs.ircmb.2021.05.004
  10. Front Mol Biosci. 2021 ;8 695601
    SMPDL3B Predicts Poor Prognosis and Contributes to Development of Acute Myeloid Leukemia.
    Huiqing Qu, Ye Zhu.
      Background: Acute myeloid leukemia (AML), characterized by the low cure rate and high relapse, urgently needs novel diagnostic or prognostic biomarkers and potential therapeutic targets. Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) is a negative regulator of Toll-like receptor signaling that plays important roles in the interface of membrane biology and innate immunity. However, the potential role of SMPDL3B in human cancer, especially in AML, is still unknown. Methods: The expression of SMPDL3B in AML samples was investigated through data collected from Gene Expression Omnibus (GEO). Association between SMPDL3B expression and clinicopathologic characteristics was analyzed with the chi-square test. Survival curves were calculated by the Kaplan-Meier method. Cox univariate and multivariate analyses were used to detect risk factors for overall survival. The biological functions of SMPDL3B in human AML were investigated both in vitro and in vivo. Results: Expression of SMPDL3B mRNA was significantly upregulated in human AML samples and closely correlated to cytogenetics risk and karyotypes. Elevated expression of SMPDL3B was associated with poor overall survival and emerged as an independent predictor for poor overall survival in human AML. Blocked SMPDL3B expression inhibited AML cells growth both in vitro and in vivo via promoting cell apoptosis. Conclusion: Taken together, our results demonstrate that SMPDL3B could be used as an efficient prognostic biomarker and represent a potential therapeutic target for human AML.
    Keywords:  SMPDL3B; acute myeloid leukemia; apoptosis; biomarker; prognosis
    DOI:  https://doi.org/10.3389/fmolb.2021.695601
  11. Oncoimmunology. 2021 ;10(1): 1945803
    Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using cross-over dual-variable domain (CODV) format for acute myeloid leukemia (AML) treatment.
    Hélène Bonnevaux, Stephane Guerif, Jana Albrecht, Erwan Jouannot, Thibaud De Gallier, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Marion Schneider, Cendrine Lemoine, Anne Caron, Céline Amara, Cédric Barrière, Justine Siavellis, Valérie Bardet, Ernesto Luna, Pankaj Agrawal, Donald R Drake, Ercole Rao, Peter Wonerow, Chantal Carrez, Véronique Blanc, Karl Hsu, Dmitri Wiederschain, Paula G Fraenkel, Angéla Virone-Oddos.
      Novel therapies are needed for effective treatment of AML. In the relapsed setting, prognosis is very poor despite salvage treatment with chemotherapy. Evidence suggests that leukemic stem cells (LSCs) cause relapse. The cell surface receptor CD123 is highly expressed in blast cells and LSCs from AML patients and is a potential therapeutic target. CD123 cross-over dual-variable domain T-cell engager (CD123-CODV-TCE) is a bispecific antibody with an innovative format. One arm targets the CD3εδ subunit of T-cell co-receptors on the surface of T cells, while the other targets CD123 on malignant cells, leading to cell-specific cytotoxic activity. Here, we describe the preclinical activity of CD123-CODV-TCE. CD123-CODV-TCE effectively binds to human and cynomolgus monkey CD3 and CD123 and is a highly potent T-cell engager. It mediates T-cell activation and T-cell-directed killing of AML cells in vitro. In vivo, CD123-CODV-TCE suppresses AML tumor growth in leukemia xenograft mouse models, where it achieves an effective half-life of 3.2 days, which is a significantly longer half-life compared to other bispecific antibodies with no associated Fc fragment. The in vitro safety profile is as expected for compounds with similar modes of action. These results suggest that CD123-CODV-TCE may be a promising therapy for patients with relapsed/refractory AML.
    Keywords:  AML; CD123; CODV; T cell engager
    DOI:  https://doi.org/10.1080/2162402X.2021.1945803
  12. Molecules. 2021 Sep 02. pii: 5332. [Epub ahead of print]26(17):
    New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway.
    Ahmed A Noser, Aboubakr H Abdelmonsef, Mohamed El-Naggar, Maha M Salem.
      Two series of novel amino acid Schiff base ligands containing heterocyclic moieties, such as quinazolinone 3-11 and indole 12-20 were successfully synthesized and confirmed by spectroscopic techniques and elemental analysis. Furthermore, all compounds were investigated in silico for their ability to inhibit mitochondrial NADH: ubiquinone oxidoreductase (complex I) by targeting the AMPK/mTOR signaling pathway and inhibiting hexokinase, a key glycolytic enzyme to prevent the Warburg effect in cancer cells. This inhibitory pathway may be an effective strategy to cause cancer cell death due to an insufficient amount of ATP. Our results revealed that, out of 18 compounds, two (11 and 20) were top-ranked as they exhibited the highest binding energies of -8.8, -13.0, -7.9, and -10.0 kcal/mol in the docking analysis, so they were then selected for in vitro assessment. Compound 11 promoted the best cytotoxic effect on MCF-7 with IC50 = 64.05 ± 0.14 μg/mL (0.135 mM) while compound 20 exhibited the best cytotoxic effect on MDA-231 with IC50 = 46.29 ± 0.09 μg/mL (0.166 mM) Compounds 11 and 20 showed significant activation of AMPK protein and oxidative stress, which led to elevated expression of p53 and Bax, reduced Bcl-2 expression, and caused cell cycle arrest at the sub-G0/G1 phase. Moreover, compounds 11 and 20 showed significant inhibition of the mTOR protein, which led to the activation of aerobic glycolysis for survival. This alternative pathway was also blocked as compounds 11 and 20 showed significant inhibitory effects on the hexokinase enzyme. These findings demonstrate that compounds 11 and 20 obeyed Lipinski's rule of five and could be used as privileged scaffolds for cancer therapy via their potential inhibition of mitochondrial complex I-associated hexokinase.
    Keywords:  NADH: ubiquinone oxidoreductase; cancer; cytotoxic activity; docking study; hexokinase
    DOI:  https://doi.org/10.3390/molecules26175332
  13. FEBS J. 2021 Sep 04.
    PPARα at the Crossroad of Metabolic-Immune Regulation in Cancer.
    Wenfeng Zeng, Xiaozhe Yin, Yunhan Jiang, Lingtao Jin, Wei Liang.
      Rewiring metabolism to sustain cell growth, division and survival is the most prominent feature of cancer cells. In particular, dysregulated lipid metabolism in cancer has received accumulating interest, since lipid molecules serve as cell membrane structure components, secondary signaling messengers, and energy sources. Given the critical role of immune cells in host defense against cancer, recent studies have revealed that immune cells compete for nutrients with cancer cells in the tumor microenvironment and accordingly develop adaptive metabolic strategies for survival at the expense of compromised immune functions. Among these strategies, lipid metabolism reprogramming toward fatty acid oxidation is closely related to the immunosuppressive phenotype of tumor infiltrated immune cells, including macrophages, dendritic cells, etc. Therefore, it is important to understand the lipid-mediated crosstalk between cancer cells and immune cells in the tumor microenvironment. Peroxisome proliferator-activated receptors (PPARs) consist of a nuclear receptor family for lipid sensing, and one of the family members PPARα is responsible for fatty acid oxidation, energy homeostasis and regulation of immune cell functions. In this review, we discuss the emerging role of PPARα-associated metabolic-immune regulation in tumor infiltrated immune cells, and key metabolic events and pathways involved, and as well as their influences on anti-tumor immunity.
    Keywords:  PPARα; fatty acid oxidation; lipid metabolism; metabolic-immune regulation; tumor-derived exosomes
    DOI:  https://doi.org/10.1111/febs.16181
  14. Int Immunol. 2021 Sep 07. pii: dxab067. [Epub ahead of print]
    Pharmacological effects on anaplerotic pathways alters the metabolic landscape in the tumor microenvironment, causing unpredictable, sustained antitumor immunity.
    Heiichiro Udono, Mikako Nishida.
      To achieve sustained antitumor immunity, tumor-infiltrating effector CD8 T lymphocytes (CD8 TILs) must be able to produce cytokines, including IFNγ and proliferate robustly within the local tumor tissue upon antigen recognition. IFNγ production by CD8 TILs depends on glycolysis, whereas their proliferation additionally requires oxidative phosphorylation (OxPhos). The level of OxPhos, and hence the oxygen consumption rate, depends on mitochondrial biogenesis and requires the loading of metabolic precursors into the tricarboxylic acid cycle to keep it functioning. This is referred to as anaplerosis. Recent advances in the field of immuno-metabolism have shown the impact of pharmacological agents on anaplerotic pathways, resulting in metabolic downregulation in tumor cells; in contrast, the agents trigger sustained antitumor immunity by upregulating both glycolysis and OxPhos in CD8 TILs. The opposing effects of pharmacological inhibition (and/or activation) on anaplerosis in tumor cells and CD8 TILs are unpredictable. Careful dissection of the underlying mechanism might confer important knowledge, helping us to step into a new era for cancer immunotherapy.
    Keywords:  immuno-metabolism; tumor immunity
    DOI:  https://doi.org/10.1093/intimm/dxab067
  15. Adv Drug Deliv Rev. 2021 Sep 01. pii: S0169-409X(21)00355-0. [Epub ahead of print] 113962
    Guiding immunotherapy combinations: who gets what?
    Michelle N Ferreira, Jennifer H Choe.
      Although PD-1 and CTLA-4 inhibitors have proven successful in a range of malignancies, there are subsets of patients that do not respond to these agents due to upregulation of adaptive and innate resistance mechanisms by the tumor and its surrounding microenvironment. As new immunotherapeutic strategies are developed, there is a need for rational implementation of novel immunotherapy combinations that target complementary mechanisms of immunotherapy resistance intrinsic to each patient and tumor type. In this short review, we cover mechanisms by which tumors evade the immune system, as well as summarize available clinical data on emerging therapeutic agents that target these defense mechanisms. Rational implementation of combination immunotherapy targeting patient- and malignancy-specific immune evasion mechanisms may thus lead to enhanced response rates and allow immunotherapy to be effective even in tumors that are historically considered poorly responsive to immunotherapy.
    Keywords:  Tumor microenvironment; cancer immunotherapy; checkpoint inhibition; immunotherapy resistance; tumor neoantigens; tumor vaccines
    DOI:  https://doi.org/10.1016/j.addr.2021.113962
  16. Front Mol Biosci. 2020 ;7 595395
    Epigenetic Therapy Promotes the Ratio of Th1/Th17 Lineage to Reverse Immune Evasion and Treat Leukemia Relapse Post-allogeneic Stem Cell Transplantation in Non-APL AML Patients.
    Yang Xi, Dai Jingying, Li Chenglong, Zheng Hong, Zhang Rong, Wang Xiaodong, Wang Chunsen, Huang Xiaobing.
      To reverse the early-stage relapse post-hematopoietic stem cell transplantation, we investigated the safety and efficacy of a new epigenetic regimen (chidamide and decitabine plus thymalfasin simultaneously) on acute myeloid leukemia patients (excluding acute promyelocytic leukemia). Twenty-four patients were enrolled in this observational study during April 2015 to May 2018. The most common adverse event was reversible CTCAE grade 2 thrombocytopenia (20/24). Strikingly, all 24 patients had response to this epigenetic regimen accompanied with decreased measurable residual disease. The overall survival rate is 79.2% (19/24), with a relapse-free survival rate of 79.2% (19/24). During this regimen treatment, Th1 cells and CD3+CD4-CD8+T cells increased, and Th17 cells decreased gradually. The status of high Th1 and low Th17 cells was still observed on the 3rd month after discontinuation of this regimen. Interestingly, the significantly elevated ratio of Th1/Th17 seemed to reflect the treatment-related immune effect, which may be a valuable marker to be monitored in the early-relapse stage for evaluating the efficacy and prognosis.
    Keywords:  Th1/Th17; epigenetic regimen; immune evasion; non-APL AML; transplant relapse
    DOI:  https://doi.org/10.3389/fmolb.2020.595395
  17. Cell Death Dis. 2021 Sep 04. 12(9): 835
    The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance.
    Kangchen Chen, Chenzhi Zhang, Sunbin Ling, Rongli Wei, Jianguo Wang, Xiao Xu.
      Quiescence has been observed in stem cells (SCs), including adult SCs and cancer SCs (CSCs). Conventional chemotherapies mostly target proliferating cancer cells, while the quiescent state favors CSCs escape to chemotherapeutic drugs, leaving risks for tumor recurrence or metastasis. The tumor microenvironment (TME) provides various signals that maintain resident quiescent CSCs, protect them from immune surveillance, and facilitates their recurrence potential. Since the TME has the potential to support and initiate stem cell-like programs in cancer cells, targeting the TME components may prove to be a powerful modality for the treatment of chemotherapy resistance. In addition, an increasing number of studies have discovered that CSCs exhibit the potential of metabolic flexibility when metabolic substrates are limited, and display increased robustness in response to stress. Accompanied by chemotherapy that targets proliferative cancer cells, treatments that modulate CSC quiescence through the regulation of metabolic pathways also show promise. In this review, we focus on the roles of metabolic flexibility and the TME on CSCs quiescence and further discuss potential treatments of targeting CSCs and the TME to limit chemotherapy resistance.
    DOI:  https://doi.org/10.1038/s41419-021-04116-6
  18. Sci Rep. 2021 Sep 09. 11(1): 18012
    DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis.
    Anna Chashchina, Melanie Märklin, Clemens Hinterleitner, Helmut R Salih, Jonas S Heitmann, Boris Klimovich.
      DNAM-1 is reportedly expressed on cytotoxic T and NK cells and, upon interaction with its ligands CD112 and CD155, plays an important role in tumor immunosurveillance. It has also been reported to be functionally expressed by myeloid cells, but expression and function on malignant cells of the myeloid lineage have not been studied so far. Here we analyzed expression of DNAM-1 in leukemic cells of acute myeloid leukemia (AML) patients. We found substantial levels of DNAM-1 to be expressed on leukemic blasts in 48 of 62 (> 75%) patients. Interaction of DNAM-1 with its ligands CD112 and CD155 induced release of the immunomodulatory cytokines IL-6, IL-8 IL-10 and TNF-α by AML cells and DNAM-1 expression correlated with a more differentiated phenotype. Multivariate analysis did not show any association of DNAM-1 positivity with established risk factors, but expression was significantly associated with clinical disease course: patients with high DNAM-1 surface levels had significantly longer progression-free and overall survival compared to DNAM-1low patients, independently whether patients had undergone allogenic stem cell transplantation or not. Together, our findings unravel a functional role of DNAM-1 in AML pathophysiology and identify DNAM-1 as a potential novel prognostic maker in AML.
    DOI:  https://doi.org/10.1038/s41598-021-97400-6
  19. Front Mol Biosci. 2021 ;8 711227
    Role of Copper on Mitochondrial Function and Metabolism.
    Lina M Ruiz, Allan Libedinsky, Alvaro A Elorza.
      Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.
    Keywords:  ROS; cancer; copper; differentiation; hematopoietic stem cells (HSCs); metabolic reprograming; mitochondria; proliferation
    DOI:  https://doi.org/10.3389/fmolb.2021.711227
  20. Free Radic Biol Med. 2021 Sep 05. pii: S0891-5849(21)00715-2. [Epub ahead of print]
    Loss of the redox mitochondrial protein mitoNEET leads to mitochondrial dysfunction in B-cell acute lymphoblastic leukemia.
    Werner J Geldenhuys, Debbie Piktel, Javohn C Moore, Stephanie L Rellick, Ethan Meadows, Mark V Pinti, John M Hollander, Amanda G Ammer, Karen H Martin, Laura F Gibson.
      B-cell acute lymphoblastic leukemia (ALL) affects both pediatric and adult patients. Chemotherapy resistant tumor cells that contribute to minimal residual disease (MRD) underlie relapse and poor clinical outcomes in a sub-set of patients. Targeting mitochondrial oxidative phosphorylation (OXPHOS) in the treatment of refractory leukemic cells is a potential novel approach to sensitizing tumor cells to existing standard of care therapeutic agents. In the current study, we have expanded our previous investigation of the mitoNEET ligand NL-1 in the treatment of ALL to interrogate the functional role of the mitochondrial outer membrane protein mitoNEET in B-cell ALL. Knockout (KO) of mitoNEET (gene: CISD1) in REH leukemic cells led to changes in mitochondrial ultra-structure and function. REH cells have significantly reduced OXPHOS capacity in the KO cells coincident with reduction in electron flow and increased reactive oxygen species. In addition, we found a decrease in lipid content in KO cells, as compared to the vector control cells was observed. Lastly, the KO of mitoNEET was associated with decreased proliferation as compared to control cells when exposed to the standard of care agent cytarabine (Ara-C). Taken together, these observations suggest that mitoNEET is essential for optimal function of mitochondria in B-cell ALL and may represent a novel anti-leukemic drug target for treatment of minimal residual disease.
    Keywords:  Chemoresistance; Glitazones; Mitochondrial dysfunction; cisd2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.09.003
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