bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–01–15
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. The Effect of Oxidative Phosphorylation on Cancer Drug Resistance.
  2. Present and Future Role of Immune Targets in Acute Myeloid Leukemia.
  3. Overview of Cancer Metabolism and Signaling Transduction.
  4. Lactic fermentation: A maladaptive mechanism and an evolutionary throwback boosting cancer drug resistance.
  5. Cancer resistance to immunotherapy: What is the role of cancer stem cells?
  6. Prediction of prognosis and immunotherapy response of amino acid metabolism genes in acute myeloid leukemia.
  7. Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia.
  8. Genetic mutations affecting mitochondrial function in cancer drug resistance.
  9. Metabolic Adaptations of Cancer in Extreme Tumor Microenvironments.
  10. Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia.
  11. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123.
  1. Cancers (Basel). 2022 Dec 22. pii: 62. [Epub ahead of print]15(1):
    The Effect of Oxidative Phosphorylation on Cancer Drug Resistance.
    Ziyi Zhao, Yong Mei, Ziyang Wang, Weiling He.
      Recent studies have shown that oxidative phosphorylation (OXPHOS) is a target for the effective attenuation of cancer drug resistance. OXPHOS inhibitors can improve treatment responses to anticancer therapy in certain cancers, such as melanomas, lymphomas, colon cancers, leukemias and pancreatic ductal adenocarcinoma (PDAC). However, the effect of OXPHOS on cancer drug resistance is complex and associated with cell types in the tumor microenvironment (TME). Cancer cells universally promote OXPHOS activity through the activation of various signaling pathways, and this activity is required for resistance to cancer therapy. Resistant cancer cells are prevalent among cancer stem cells (CSCs), for which the main metabolic phenotype is increased OXPHOS. CSCs depend on OXPHOS to survive targeting by anticancer drugs and can be selectively eradicated by OXPHOS inhibitors. In contrast to that in cancer cells, mitochondrial OXPHOS is significantly downregulated in tumor-infiltrating T cells, impairing antitumor immunity. In this review, we summarize novel research showing the effect of OXPHOS on cancer drug resistance, thereby explaining how this metabolic process plays a dual role in cancer progression. We highlight the underlying mechanisms of metabolic reprogramming in cancer cells, as it is vital for discovering new drug targets.
    Keywords:  cancer immunity; glycolysis; metabolism; oxidative phosphorylation; resistance
    DOI:  https://doi.org/10.3390/cancers15010062
  2. Cancers (Basel). 2022 Dec 30. pii: 253. [Epub ahead of print]15(1):
    Present and Future Role of Immune Targets in Acute Myeloid Leukemia.
    Daniela Damiani, Mario Tiribelli.
      It is now well known that the bone marrow (BM) cell niche contributes to leukemogenesis, but emerging data support the role of the complex crosstalk between AML cells and the BM microenvironment to induce a permissive immune setting that protects leukemic stem cells (LSCs) from therapy-induced death, thus favoring disease persistence and eventual relapse. The identification of potential immune targets on AML cells and the modulation of the BM environment could lead to enhanced anti-leukemic effects of drugs, immune system reactivation, and the restoration of AML surveillance. Potential targets and effectors of this immune-based therapy could be monoclonal antibodies directed against LSC antigens such as CD33, CD123, and CLL-1 (either as direct targets or via several bispecific T-cell engagers), immune checkpoint inhibitors acting on different co-inhibitory axes (alone or in combination with conventional AML drugs), and novel cellular therapies such as chimeric antigen receptor (CAR) T-cells designed against AML-specific antigens. Though dozens of clinical trials, mostly in phases I and II, are ongoing worldwide, results have still been negatively affected by difficulties in the identification of the optimal targets on LSCs.
    Keywords:  acute myeloid leukemia; drug resistance; immune escape; immune therapy
    DOI:  https://doi.org/10.3390/cancers15010253
  3. Int J Mol Sci. 2022 Dec 20. pii: 12. [Epub ahead of print]24(1):
    Overview of Cancer Metabolism and Signaling Transduction.
    Hee-Suk Chae, Seong-Tshool Hong.
      Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism.
    Keywords:  ROS; aerobic glycolysis; anti-cancer drug; cancer; glutamine; metabolism; redox; signal transduction
    DOI:  https://doi.org/10.3390/ijms24010012
  4. Biochimie. 2023 Jan 10. pii: S0300-9084(23)00005-6. [Epub ahead of print]
    Lactic fermentation: A maladaptive mechanism and an evolutionary throwback boosting cancer drug resistance.
    Davide Gnocchi, Carlo Sabbà, Antonio Mazzocca.
      After four decades of research primarily focused on tumour genetics, the importance of metabolism in tumour biology is receiving renewed attention. Cancer cells undergo energy, biosynthetic and metabolic rewiring, which involves several pathways with a prevalent change from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, known as the Warburg effect. During carcinogenesis, microenvironmental changes can trigger the transition from OXPHOS to lactic acid fermentation, an ancient form of energy supply, mimicking the behaviour of certain anaerobic unicellular organisms according to "atavistic" models of cancer. However, the role of this transition as a mechanism of cancer drug resistance is unclear. Here, we hypothesise that the metabolic rewiring of cancer cells to fermentation can be triggered, enhanced, and sustained by exposure to chronic or high-dose chemotherapy, thereby conferring resistance to drug therapy. We try to expand on the idea that metabolic reprogramming from OXPHOS to lactate fermentation in drug-resistant tumour cells occurs as a general phenotypic mechanism in any type of cancer, regardless of tumour cell heterogeneity, biodiversity, and genetic characteristics. This metabolic response may therefore represent a common feature in cancer biology that could be exploited for therapeutic purposes to overcome chemotherapy resistance, which is currently a major challenge in cancer treatment.
    Keywords:  Atavistic throwback; Drug resistance; Lactic acid fermentation; Maladaptive evolution; Metabolic switch
    DOI:  https://doi.org/10.1016/j.biochi.2023.01.005
  5. Cancer Drug Resist. 2022 ;5(4): 981-994
    Cancer resistance to immunotherapy: What is the role of cancer stem cells?
    Gourab Gupta, George Merhej, Shakthika Saravanan, Hexin Chen.
      Immunotherapy is an emerging form of cancer therapy that is associated with promising outcomes. However, most cancer patients either do not respond to immunotherapy or develop resistance to treatment. The resistance to immunotherapy is poorly understood compared to chemotherapy and radiotherapy. Since immunotherapy targets cells within the tumor microenvironment, understanding the behavior and interactions of different cells within that environment is essential to adequately understand both therapy options and therapy resistance. This review focuses on reviewing and analyzing the special features of cancer stem cells (CSCs), which we believe may contribute to cancer resistance to immunotherapy. The mechanisms are classified into three main categories: mechanisms related to surface markers which are differentially expressed on CSCs and help CSCs escape from immune surveillance and immune cells killing; mechanisms related to CSC-released cytokines which can recruit immune cells and tame hostile immune responses; and mechanisms related to CSC metabolites which modulate the activities of infiltrated immune cells in the tumor microenvironment. This review also discusses progress made in targeting CSCs with immunotherapy and the prospect of developing novel cancer therapies.
    Keywords:  Immunotherapy; cancer stem cells; immunotherapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.20517/cdr.2022.19
  6. Front Nutr. 2022 ;9 1056648
    Prediction of prognosis and immunotherapy response of amino acid metabolism genes in acute myeloid leukemia.
    Hui Zhou, Fengjuan Wang, Ting Niu.
       Background: Amino acid (AA) metabolism plays a crucial role in cancer. However, its role in acute myeloid leukemia (AML) is still unavailable. We screened out AA metabolic genes, which related to prognosis, and analyzed their correlation with tumor immune microenvironment in AML.
    Methods: We evaluated 472 amino acid metabolism-related genes in 132 AML patients. The predictive risk model was developed according to differentially expressed genes, univariate Cox and LASSO analyses. We validated the risk signature by survival analysis and independence tests. Single-sample gene set enrichment analysis (ssGSEA), tumor immune microenvironment (TME), tumor mutation burden (TMB), functional enrichment, and the IC50 of drugs were assessed to explore the correlations among the risk model, immunity, and drug sensitivity of AML.
    Results: Six amino acid metabolism-related genes were confirmed to develop the risk model, including TRH, HNMT, TFEB, SDSL, SLC43A2, and SFXN3. The high-risk subgroup had an immune "hot" phenotype and was related to a poor prognosis. The high-risk group was also associated with more activity of immune cells, such as Tregs, had higher expression of some immune checkpoints, including PD1 and CTLA4, and might be more susceptible to immunotherapy. Xenobiotic metabolism, the reactive oxygen species (ROS) pathway, fatty acid metabolism, JAK/STAT3, and the inflammatory response were active in the high-risk subgroup. Furthermore, the high-risk subgroup was sensitive to sorafenib, selumetinib, and entospletinib. ssGSEA discovered that the processes of glutamine, arginine, tryptophan, cysteine, histidine, L-serine, isoleucine, threonine, tyrosine, and L-phenylalanine metabolism were more active in the high-risk subgroup.
    Conclusion: This study revealed that AA metabolism-related genes were correlated with the immune microenvironment of AML patients and could predict the prognosis and immunotherapy response of AML patients.
    Keywords:  acute myeloid leukemia; amino acid metabolism; immunotherapy; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fnut.2022.1056648
  7. Int J Mol Sci. 2022 Dec 29. pii: 563. [Epub ahead of print]24(1):
    Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia.
    Kathryn A Skelding, Daniel L Barry, Danielle Z Theron, Lisa F Lincz.
      Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.
    Keywords:  AML; acute myeloid leukaemia; bone marrow microenvironment; bone marrow niche; drug targets
    DOI:  https://doi.org/10.3390/ijms24010563
  8. Genes Genomics. 2023 Jan 07.
    Genetic mutations affecting mitochondrial function in cancer drug resistance.
    Chanhaeng Lee, Sang-Hee Park, Sungjoo Kim Yoon.
      Mitochondria are organelles that serve as a central hub for physiological processes in eukaryotes, including production of ATP, regulation of calcium dependent signaling, generation of ROS, and regulation of apoptosis. Cancer cells undergo metabolic reprogramming in an effort to support their increasing requirements for cell survival, growth, and proliferation, and mitochondria have primary roles in these processes. Because of their central function in survival of cancer cells and drug resistance, mitochondria are an important target in cancer therapy and many drugs targeting mitochondria that target the TCA cycle, apoptosis, metabolic pathway, and generation of ROS have been developed. Continued use of mitochondrial-targeting drugs can lead to resistance due to development of new somatic mutations. Use of drugs is limited due to these mutations, which have been detected in mitochondrial proteins. In this review, we will focus on genetic mutations in mitochondrial target proteins and their function in induction of drug-resistance.
    Keywords:  Chemotherapy; Drug resistance; Mitochondria targeting drugs; Mutations in mitochondrial proteins
    DOI:  https://doi.org/10.1007/s13258-022-01359-1
  9. Cancer Sci. 2023 Jan 11.
    Metabolic Adaptations of Cancer in Extreme Tumor Microenvironments.
    Ryuichi Nakahara, Keisuke Maeda, Sho Aki, Tsuyoshi Osawa.
      Cancer cells are highly heterogeneous in order to adapt to extreme tumor microenvironments. Tumor microenvironments challenge cancer cells via hypoxia, nutrition starvation, and acidic pH, promoting invasion and metastasis concomitant with genetic, epigenetic, and metabolic alterations. Metabolic adaptation to an extreme tumor microenvironment could allow cancer cells to evade cell death and immune responses, as well as resulting in drug resistance, recurrence and poor patient prognosis. Therefore, elucidation of the metabolic adaptation of malignant cancer cells within tumor microenvironments is necessary, however, most are still elusive. Recently, adaptation of cancer cells within the tumor microenvironment can be analyzed via cell-cell interactions at the single cell level. In addition, information into organelle-organelle interactions has recently been obtained. These cell-cell, and organelle-organelle interactions demonstrate potential as new cancer therapy targets, as they play essential roles in the metabolic adaptation of cancer cells to the tumor microenvironment. In this manuscript, we review (1) metabolic adaptations within tumor microenvironments through (2) cell-to-cell, and (3) organelle-organelle metabolic interactions.
    Keywords:  Cancer Metabolism; Hypoxia; Nutrient starvation; Organelle; acidic pH
    DOI:  https://doi.org/10.1111/cas.15722
  10. Blood Adv. 2023 Jan 09. pii: bloodadvances.2022008854. [Epub ahead of print]
    Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia.
    Yazad Darius Irani, Chung Hoow Kok, Jade Clarson, Naranie Shanmuganathan, Susan Branford, David T Yeung, David M Ross, Timothy P Hughes, Agnes Sm Yong.
      Dysregulation of immune checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), but their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed PD-1, TIM-3, CTLA-4, LAG-3 and TIGIT expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 who sustained treatment-free remission (TFR), 22 who experienced molecular relapse (MolR)). We confirmed our previous finding that absolute numbers of T-regs are increased in MolR patients compared to TFR. The immune checkpoint receptors PD-1, CTLA-4, LAG-3 and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T-cells (CD3+), and T-cell subsets including, CD4+T-cells, CD8+T-cells, and T-regs, in patients who relapsed in comparison to those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available datasets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in CML patients stopping TKI, whilst concomitantly targeting leukemic stem cells, and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in CML patients.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008854
  11. Nat Biotechnol. 2023 Jan 12.
    Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123.
    Laurent Gauthier, Angela Virone-Oddos, Jochen Beninga, Benjamin Rossi, Céline Nicolazzi, Céline Amara, Audrey Blanchard-Alvarez, Nicolas Gourdin, Jacqueline Courta, Alexandra Basset, Magali Agnel, Franceline Guillot, Gwendoline Grondin, Hélène Bonnevaux, Anne-Laure Bauchet, Ariane Morel, Yannis Morel, Marielle Chiron, Eric Vivier.
      CD123, the alpha chain of the IL-3 receptor, is an attractive target for acute myeloid leukemia (AML) treatment. However, cytotoxic antibodies or T cell engagers targeting CD123 had insufficient efficacy or safety in clinical trials. We show that expression of CD64, the high-affinity receptor for human IgG, on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro. We engineer a trifunctional natural killer cell engager (NKCE) that targets CD123 on AML blasts and NKp46 and CD16a on NK cells (CD123-NKCE). CD123-NKCE has potent antitumor activity against primary AML blasts regardless of CD64 expression and induces NK cell activation and cytokine secretion only in the presence of AML cells. Its antitumor activity in a mouse CD123+ tumor model exceeds that of the benchmark ADCC-enhanced antibody. In nonhuman primates, it had prolonged pharmacodynamic effects, depleting CD123+ cells for more than 10 days with no signs of toxicity and very low inflammatory cytokine induction over a large dose range. These results support clinical development of CD123-NKCE.
    DOI:  https://doi.org/10.1038/s41587-022-01626-2
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