bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–02–12
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia.
  2. Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.
  3. Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.
  4. A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia.
  5. A reduced model of cell metabolism to revisit the glycolysis-OXPHOS relationship in the deregulated tumor microenvironment.
  6. CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm.
  7. Manipulation of metabolic pathways to promote stem-like and memory T cell phenotypes for immunotherapy.
  8. The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
  9. Immune therapy: a new therapy for acute myeloid leukemia.
  10. Modulating Glycolysis to Improve Cancer Therapy.
  1. Blood Adv. 2023 Feb 06. pii: bloodadvances.2022008405. [Epub ahead of print]
    TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia.
    Teppei Sakoda, Yoshikane Kikushige, Toshihiro Miyamoto, Hidetoshi Irifune, Takuya Harada, Kiwamu Hatakeyama, Yuya Kunisaki, Koji Kato, Koichi Akashi.
      The activation of β-catenin plays critical roles in normal stem cell function, and when aberrantly activated, maintenance and enhancement of cancer stemness in many solid cancers. The aberrant β-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast to such solid tumors. In this study, we showed that the AML-specific autocrine loop constituted of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of leukemic stem cells (LSCs), independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 (SH2) domain of TIM-3 to recruit hematopoietic cell kinase (HCK), an Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL-receptor related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally employed in immature LSCs compared to TIM-3-expressed differentiated AML blasts and exhausted T-cells. These data suggest that human AML LSCs constitutively activates β-catenin through utilizing the autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008405
  2. Leukemia. 2023 Feb 04.
    Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.
    Clement Larrue, Sarah Mouche, Shan Lin, Federico Simonetta, Nastassja K Scheidegger, Laury Poulain, Rudy Birsen, Jean-Emmanuel Sarry, Kimberly Stegmaier, Jerome Tamburini.
      Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.
    DOI:  https://doi.org/10.1038/s41375-023-01835-x
  3. Int J Mol Sci. 2023 Jan 25. pii: 2337. [Epub ahead of print]24(3):
    Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.
    Francesco Pacifico, Antonio Leonardi, Elvira Crescenzi.
      In this review we focus on the role of glutamine in control of cancer stem cell (CSC) fate. We first provide an overview of glutamine metabolism, and then summarize relevant studies investigating how glutamine metabolism modulates the CSC compartment, concentrating on solid tumors. We schematically describe how glutamine in CSC contributes to several metabolic pathways, such as redox metabolic pathways, ATP production, non-essential aminoacids and nucleotides biosynthesis, and ammonia production. Furthermore, we show that glutamine metabolism is a key regulator of epigenetic modifications in CSC. Finally, we briefly discuss how cancer-associated fibroblasts, adipocytes, and senescent cells in the tumor microenvironment may indirectly influence CSC fate by modulating glutamine availability. We aim to highlight the complexity of glutamine's role in CSC, which supports our knowledge about metabolic heterogeneity within the CSC population.
    Keywords:  adipocytes; cancer stem cells; cancer-associated fibroblasts; glutamine; metabolism; senescent cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms24032337
  4. Front Immunol. 2023 ;14 1108200
    A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia.
    Başak Aru, Cemil Pehlivanoğlu, Zeynep Dal, Nida Nur Dereli-Çalışkan, Ege Gürlü, Gülderen Yanıkkaya-Demirel.
      Acute myeloid leukemia (AML) arises from the cells of myeloid lineage and is the most frequent leukemia type in adulthood accounting for about 80% of all cases. The most common treatment strategy for the treatment of AML includes chemotherapy, in rare cases radiotherapy and stem cell and bone marrow transplantation are considered. Immune checkpoint proteins involve in the negative regulation of immune cells, leading to an escape from immune surveillance, in turn, causing failure of tumor cell elimination. Immune checkpoint inhibitors (ICIs) target the negative regulation of the immune cells and support the immune system in terms of anti-tumor immunity. Bone marrow microenvironment (BMM) bears various blood cell lineages and the interactions between these lineages and the noncellular components of BMM are considered important for AML development and progression. Administration of ICIs for the AML treatment may be a promising option by regulating BMM. In this review, we summarize the current treatment options in AML treatment and discuss the possible application of ICIs in AML treatment from the perspective of the regulation of BMM.
    Keywords:  acute myeloid leukemia; bone marrow microenvironment; immune checkpoint inhibitors (ICI); immune checkpoint proteins (ICP); tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1108200
  5. J Theor Biol. 2023 Feb 03. pii: S0022-5193(23)00030-9. [Epub ahead of print] 111434
    A reduced model of cell metabolism to revisit the glycolysis-OXPHOS relationship in the deregulated tumor microenvironment.
    Pierre Jacquet, Angélique Stéphanou.
      Cancer cells metabolism focuses the interest of the cancer research community. Although this process is intensely studied experimentally, there are very few theoretical models that address this issue. One of the main reasons is the extraordinary complexity of the metabolism that involves numerous interdependent regulatory networks which makes the computational recreation of this complexity illusory. In this study we propose a reduced model of the metabolism which focuses on the interrelation of the three main energy metabolites which are oxygen, glucose and lactate in order to better understand the dynamics of the core system of the glycolysis-OXPHOS relationship. So simple as it is, the model highlights the main rules allowing the cell to dynamically adapt its metabolism to its changing environment. It also makes it possible to address this impact at the tissue scale. The simulations carried out in a spheroid show non-trivial spatial heterogeneity of energy metabolism. It further suggests that the metabolic features that are commonly attributed to cancer cells are not necessarily due to an intrinsic abnormality of the cells. They can emerge spontaneously due to the deregulated over-acidic environment.
    Keywords:  Acidity; Energetic needs; Pyruvate-lactate; Theoretical model; Warburg effect
    DOI:  https://doi.org/10.1016/j.jtbi.2023.111434
  6. Int J Mol Sci. 2023 Feb 01. pii: 2718. [Epub ahead of print]24(3):
    CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm.
    Elvira Pelosi, Germana Castelli, Ugo Testa.
      In spite of consistent progress at the level of basic research and of clinical treatment, acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. To improve the outcomes of these patients, it is necessary to identify new therapeutic targets. IL3RA (CD123, alpha subunit of the interleukin 3 receptor) is a cell membrane protein overexpressed in several hematologic malignancies, including AML blastic plasmocytoid dendritic cell neoplasms (BPDCN). Given the higher expression of CD123 on leukemic cells compared to normal hematopoietic cells and its low/absent expression on normal hematopoietic stem cells, it appears as a suitable and attractive target for therapy. Various drugs targeting CD123 have been developed and evaluated at clinical level: interleukin-3 conjugated with diphtheria toxin; naked neutralizing anti-CD123 antibodies; drug-antibody conjugates; bispecific antibodies targeting both CD123 and CD3; and chimeric antigen receptor (CAR) T cells engineered to target CD123. Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.
    Keywords:  CD123; acute myeloid leukemia; blastic plasmocytoid dendritic cell neoplasm; interleukin-3; interleukin-3 receptor; targeted therapy
    DOI:  https://doi.org/10.3390/ijms24032718
  7. Front Immunol. 2022 ;13 1061411
    Manipulation of metabolic pathways to promote stem-like and memory T cell phenotypes for immunotherapy.
    Michael D Claiborne.
      Utilizing the immune system's capacity to recognize and kill tumor cells has revolutionized cancer therapy in recent decades. Phenotypic study of antitumor T cells supports the principle that superior tumor control is achieved by cells with more long-lived memory or stem-like properties as compared to terminally differentiated effector cells. In this Mini-Review, we explore recent advances in profiling the different metabolic programs that both generate and define subsets of memory T cells. We additionally discuss new experimental approaches that aim to maximize the durability and sustained antitumor response associated with memory T cells within the unique immunosuppressive conditions of the tumor microenvironment, such as engineered attempts to overcome hypoxia-induced changes in mitochondrial function, the inhibitory effects of tumor metabolites, and exploitation of more recently-defined metabolic pathways controlling T cell memory fate such as glycogen metabolism.
    Keywords:  CAR T cancer therapy; T cell memory; adoptive cell immunotherapy; immunology; metabolism; tumor immunology
    DOI:  https://doi.org/10.3389/fimmu.2022.1061411
  8. Mol Cells. 2023 Feb 09.
    The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
    Min-Ji Kim, Hoyul Lee, Dipanjan Chanda, Themis Thoudam, Hyeon-Ji Kang, Robert A Harris, In-Kyu Lee.
      Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca2+ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.
    Keywords:  T cell; macrophage; mitochondria quality control; mitochondria-associated membranes; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.14348/molcells.2023.2128
  9. Blood Sci. 2023 Jan;5(1): 15-24
    Immune therapy: a new therapy for acute myeloid leukemia.
    Chen Tian, Zehui Chen.
      Although complete remission could be achieved in about 60%-70% of acute myeloid leukemia (AML) patients after conventional chemotherapy, relapse and the state of being refractory to treatment remain the main cause of death. In addition, there is a great need for less intensive regimens for all medically frail patients (both due to age/comorbidity and treatment-related). Immune therapy anticipates improved prognosis and reduced toxicities, which may offer novel therapeutic rationales. However, one of the major difficulties in developing immune therapies against AML is that the target antigens are also significantly expressed on healthy hematopoietic stem cells; B-cell malignancies are different because CD20/CD19/healthy B-cells are readily replaceable. Only the anti-CD33 antibody-drug conjugate gemtuzumab-ozogamicin is approved by the FDA for AML. Thus, drug development remains extremely active, although it is still in its infancy. This review summarizes the clinical results of immune therapeutic agents for AML, such as antibody-based drugs, chimeric antigen receptor therapy, checkpoint inhibitors, and vaccines.
    Keywords:  Acute myeloid leukemia; Antibody-based drugs; Checkpoint inhibitors; Chimeric antigen receptor therapy; Vaccine
    DOI:  https://doi.org/10.1097/BS9.0000000000000140
  10. Int J Mol Sci. 2023 Jan 30. pii: 2606. [Epub ahead of print]24(3):
    Modulating Glycolysis to Improve Cancer Therapy.
    Chaithanya Chelakkot, Vipin Shankar Chelakkot, Youngkee Shin, Kyoung Song.
      Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.
    Keywords:  cancer metabolism; combination therapy; glycolysis
    DOI:  https://doi.org/10.3390/ijms24032606
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