bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–12–19
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases.
  2. Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.
  3. Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence.
  4. The mitochondrial copper chaperone COX11 has an additional role in cellular redox homeostasis.
  5. IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.
  6. Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy.
  7. CD99 in Malignant Hematopoiesis.
  8. Increased TOX expression concurrent with PD-1, Tim-3, and CD244 expression in T cells from patients with acute myeloid leukemia.
  1. Front Genet. 2021 ;12 785153
    Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases.
    Xin Cai, Huajie Zhan, Yuguang Ye, Jinjin Yang, Minghui Zhang, Jing Li, Yuan Zhuang.
      The inhibitory regulators, known as immune checkpoints, prevent overreaction of the immune system, avoid normal tissue damage, and maintain immune homeostasis during the antimicrobial or antiviral immune response. Unfortunately, cancer cells can mimic the ligands of immune checkpoints to evade immune surveillance. Application of immune checkpoint blockade can help dampen the ligands expressed on cancer cells, reverse the exhaustion status of effector T cells, and reinvigorate the antitumor function. Here, we briefly introduce the structure, expression, signaling pathway, and targeted drugs of several inhibitory immune checkpoints (PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, and IDO1). And we summarize the application of immune checkpoint inhibitors in tumors, such as single agent and combination therapy and adverse reactions. At the same time, we further discussed the correlation between immune checkpoints and microorganisms and the role of immune checkpoints in microbial-infection diseases. This review focused on the current knowledge about the role of the immune checkpoints will help in applying immune checkpoints for clinical therapy of cancer and other diseases.
    Keywords:  PD-1/PD-L1; cancer; immune checkpoint; immunotherapy; microbiome
    DOI:  https://doi.org/10.3389/fgene.2021.785153
  2. J Exp Clin Cancer Res. 2021 Dec 14. 40(1): 393
    Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.
    Liwei Lang, Fang Wang, Zhichun Ding, Xiangdong Zhao, Reid Loveless, Jin Xie, Chloe Shay, Peng Qiu, Yonggang Ke, Nabil F Saba, Yong Teng.
       BACKGROUND: Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits.
    METHODS: A series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate.
    RESULTS: We show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC.
    CONCLUSIONS: These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.
    Keywords:  CB-839; CPI-613; Combined targeting; GLS1; Glutaminolysis; HNSCC
    DOI:  https://doi.org/10.1186/s13046-021-02207-y
  3. EMBO Rep. 2021 Dec 16. e54384
    Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence.
    Leal Oburoglu, Els Mansell, Isaac Canals, Valgardur Sigurdsson, Carolina Guibentif, Shamit Soneji, Niels-Bjarne Woods.
      During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. Hematopoietic stem cells (HSCs) emerge from hemogenic endothelial (HE) cells, through endothelial-to-hematopoietic transition (EHT). In the adult, HSC quiescence, maintenance, and differentiation are closely linked to changes in metabolism. However, metabolic processes underlying the emergence of HSCs from HE cells remain unclear. Here, we show that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation toward specific hematopoietic lineages during human EHT. In both in vitro and in vivo settings, steering pyruvate use toward glycolysis or OXPHOS differentially skews the hematopoietic output of HE cells toward either an erythroid fate with primitive phenotype, or a definitive lymphoid fate, respectively. We demonstrate that glycolysis-mediated differentiation of HE toward primitive erythroid hematopoiesis is dependent on the epigenetic regulator LSD1. In contrast, OXPHOS-mediated differentiation of HE toward definitive hematopoiesis is dependent on cholesterol metabolism. Our findings reveal that during EHT, metabolism is a major regulator of primitive versus definitive hematopoietic differentiation.
    Keywords:  OXPHOS; endothelial-to-hematopoietic transition; glycolysis; hematopoiesis; pyruvate metabolism
    DOI:  https://doi.org/10.15252/embr.202154384
  4. PLoS One. 2021 ;16(12): e0261465
    The mitochondrial copper chaperone COX11 has an additional role in cellular redox homeostasis.
    Ivan Radin, Luise Kost, Uta Gey, Iris Steinebrunner, Gerhard Rödel.
      Mitochondria are sites of cellular respiration, which is accompanied by the generation of dangerous reactive oxygen species (ROS). Cells have multiple mechanisms to mitigate the dangers of ROS. Here we investigate the involvement of the COX complex assembly chaperone COX11 (cytochrome c oxidase 11) in cellular redox homeostasis, using homologs from the flowering plant Arabidopsis thaliana (AtCOX11) and yeast Saccharomyces cerevisiae (ScCOX11). We found that AtCOX11 is upregulated in Arabidopsis seedlings in response to various oxidative stresses, suggesting a defensive role. In line with this, the overexpression of either AtCOX11 or ScCOX11 reduced ROS levels in yeast cells exposed to the oxidative stressor paraquat. Under normal growth conditions, both Arabidopsis and yeast COX11 overexpressing cells had the same ROS levels as the corresponding WT. In contrast, the COX11 knock-down and knock-out in Arabidopsis and yeast, respectively, significantly reduced ROS levels. In yeast cells, the ScCOX11 appears to be functionally redundant with superoxide dismutase 1 (ScSOD1), a superoxide detoxifying enzyme. The ΔSccox11ΔScsod1 mutants had dramatically reduced growth on paraquat, compared with the WT or single mutants. This growth retardation does not seem to be linked to the status of the COX complex and cellular respiration. Overexpression of putatively soluble COX11 variants substantially improved the resistance of yeast cells to the ROS inducer menadione. This shows that COX11 proteins can provide antioxidative protection likely independently from their COX assembly function. The conserved Cys219 (in AtCOX11) and Cys208 (in ScCOX11) are important for this function. Altogether, these results suggest that COX11 homologs, in addition to participating in COX complex assembly, have a distinct and evolutionary conserved role in protecting cells during heightened oxidative stress.
    DOI:  https://doi.org/10.1371/journal.pone.0261465
  5. FASEB J. 2022 Jan;36(1): e22062
    IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.
    Whitney L Stuard, Rossella Titone, Danielle M Robertson.
      Mitochondrial dysfunction or loss of homeostasis is a central hallmark of many human diseases. Mitochondrial homeostasis is mediated by multiple quality control mechanisms including mitophagy, a form of selective autophagy that recycles terminally ill or dysfunctional mitochondria in order to preserve mitochondrial integrity. Our prior studies have shown that members of the insulin-like growth factor (IGF) family localize to the mitochondria and may play important roles in mediating mitochondrial health in the corneal epithelium, an integral tissue that is required for the maintenance of optical transparency and vision. Importantly, the IGF-binding protein-3, IGFBP-3, is secreted by corneal epithelial cells in response to stress and functions to mediate intracellular receptor trafficking in this cell type. In this study, we demonstrate a novel role for IGFBP-3 in mitochondrial homeostasis through regulation of the short isoform (s)BNIP3L/NIX mitophagy receptor in corneal epithelial cells and extend this finding to non-ocular epithelial cells. We further show that IGFBP-3-mediated control of mitochondrial homeostasis is associated with alterations in lamellar cristae morphology and mitochondrial dynamics. Interestingly, both loss and gain of function of IGFBP-3 drive an increase in mitochondrial respiration. This increase in respiration is associated with nuclear accumulation of IGFBP-3. Taken together, these findings support a novel role for IGFBP-3 as a key mediator of mitochondrial health in mucosal epithelia through the regulation of mitophagy and mitochondrial morphology.
    Keywords:  autophagy; insulin-like growth factor type 1 receptor; mTOR; metabolism; mitochondria
    DOI:  https://doi.org/10.1096/fj.202100710RR
  6. Front Cell Dev Biol. 2021 ;9 767466
    Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy.
    Myeong Joon Kim, Sang-Jun Ha.
      In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy. Immune checkpoint receptors (ICRs) expressed in effector immune cells inhibit their effector function via direct interaction with immune checkpoint ligands (ICLs) expressed in tumor cells. Therefore, blocking ICRs or ICLs has been developed as a promising cancer immunotherapy by reinvigorating the function of effector immune cells. Among the ICRs, programmed cell death 1 (PD-1) has mainly been antagonized to enhance the survival of human patients with cancer by restoring the function of tumor-infiltrating (TI) CD8+ T cells. It has been demonstrated that PD-1 is expressed not only in TI CD8+ T cells, but also in other TI immune cells and even tumor cells. While PD-1 suppresses the function of TI CD8+ T cells, it is controversial whether PD-1 suppresses or amplifies the suppressive function of TI-suppressive immune cells (e.g., regulatory T cells, tumor-associated macrophages, and myeloid cells). There is also controversy regarding the role of tumor-expressing PD-1. Therefore, a precise understanding of the expression pattern and function of PD-1 in each cell subset is important for improving the efficacy of cancer immunotherapy. Here, we review the differential role of PD-1 expressed by various TI immune cells and tumor cells. We focused on how cell-type-specific ablation or blockade of PD-1 affects tumor growth in a murine tumor model. Furthermore, we will also describe how the blockade of PD-1 acts on TI immune cells in human patients with cancer.
    Keywords:  cancer immunotherapy; functional restoration; programmed cell death protein 1 (PD-1); tumor microenvironment; tumor-infiltrating effector cells; tumor-infiltrating suppressive cells
    DOI:  https://doi.org/10.3389/fcell.2021.767466
  7. Exp Hematol. 2021 Dec 14. pii: S0301-472X(21)00822-5. [Epub ahead of print]
    CD99 in Malignant Hematopoiesis.
    Atham Ali, Pooja Vaikari, Houda Alachkar.
      The CD99 gene encodes a transmembrane protein that is involved in cell differentiation, adhesion, migration, and protein trafficking. CD99 is differentially expressed on the surface of hematopoietic cells both in the myeloid and lymphoid lineages. CD99 has two isoforms, the long and short isoforms that play different roles depending on the cellular context. There has been extensive evidence supporting the role of CD99 in myeloid and lymphoblastic leukemias. Here we review research findings related to the CD99 in malignant hematopoiesis. We also summarize the significance of CD99 as a therapeutic target in hematological malignancies.
    Keywords:  Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Antibody; CD99; Chronic Lymphocytic Leukemia (CLL); Chronic Myeloid Leukemia (CML); Hematological Malignancies; scFv
    DOI:  https://doi.org/10.1016/j.exphem.2021.12.363
  8. Cytometry B Clin Cytom. 2021 Dec 16.
    Increased TOX expression concurrent with PD-1, Tim-3, and CD244 expression in T cells from patients with acute myeloid leukemia.
    Shuxin Huang, Chaofeng Liang, Yujie Zhao, Tairan Deng, Jiaxiong Tan, Xianfeng Zha, Yangqiu Li, Shaohua Chen.
       BACKGROUND: T cell dysregulation is a common event in leukemia. Recent findings have indicated that aberrant expression of immune checkpoint proteins may be associated with disease relapse and progression in acute myeloid leukemia (AML). TOX, a transcription factor in the HMG-box protein superfamily, was found to be a potential target for immunotherapy not only in solid tumors but also in hematological malignancies. However, little is known about TOX expression and co-expression with immune checkpoint proteins or the exhausted phenotype in the T cell subsets in AML. Thus, in this study, we analyzed TOX expression and co-expression with PD-1, Tim-3, and CD244 in T cells.
    METHODS: TOX expression and co-expression with PD-1, Tim-3, and CD244 in CD3+, CD4+, regulatory T (Treg), and CD8+ T cells were analyzed by multi-color fluorescent flow cytometry in peripheral blood (PB) and bone marrow (BM) samples from patients with de novo AML and AML in complete remission (CR) and healthy individuals (HIs).
    RESULTS: A significantly increased percentage of TOX+CD3+, CD4+, and CD8+ T cells was found in PB from patients with de novo AML in comparison with HIs. Double-positive TOX+CD244+, TOX+PD-1+, and TOX+Tim-3+ T cells markedly increased in the CD3+, CD4+, and CD8+ T cell populations in de novo AML patients compared with HIs, and similar trends were demonstrated for TOX+Tim-3+CD3+/CD4+/CD8+ T cells in de novo AML compared with AML-CR patients. In addition, the number of TOX+, TOX+PD-1+, and TOX+Tim-3+Treg cells significantly increased in de novo AML patients compared with HIs, and TOX+PD-1+Treg cells were higher in de novo AML compared with AML-CR patients. Moreover, TOX positively correlated with Tim-3 expression in CD8+ and Treg cells, and a positive correlation between the expression of TOX+ CD4+ and CD244+CD4+ T cells was found. Furthermore, an increased percentage of TOX+Tim-3+ T cells in BM was also found in de novo AML patients compared with HIs.
    CONCLUSIONS: Increased TOX concurrent with PD-1, Tim-3, and CD244 in T cells may contribute to T cell exhaustion and impair their function in AML. Such exhausted T cells may be partially revised when AML patients achieve CR after chemotherapy. TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in AML.
    Keywords:  AML; PD-1; T cell exhaustion; T cell subset; TOX; Tim-3
    DOI:  https://doi.org/10.1002/cyto.b.22049
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