bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–10–09
fiveteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. [Energy metabolism of acute myeloid leukemia cells in the bone marrow microenvironment].
  2. Lessons to cancer from studies of leukemia and hematopoiesis.
  3. MCL-1 is a master regulator of cancer dependency on fatty acid oxidation.
  4. Differential glutamine metabolism in the tumor microenvironment - studies in diversity and heterogeneity: A mini-review.
  5. [Novel therapies in AML and their resistance mechanisms].
  6. Investigating myeloid cells? Go with the flow.
  7. [Bone Marrow Osteoblasts Promotes the Proliferation Leukemia Stem Cell by Up-regulating Interleukin-1].
  8. IL-7: Comprehensive review.
  9. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
  10. Stem Cells: Therapeutic implications in chemotherapy and radiotherapy resistance in Cancer Therapy.
  11. Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy.
  12. Type I interferon induces cancer stem cells-mediated chemotherapy resistance.
  13. Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.
  14. Editorial: Microenvironment-derived stem cell plasticity-volume II.
  15. Biomarkers of related driver genes predict anti-tumor efficacy of immune checkpoint inhibitors.
  1. Rinsho Ketsueki. 2022 ;63(9): 1046-1051
    [Energy metabolism of acute myeloid leukemia cells in the bone marrow microenvironment].
    Yoko Tabe.
      In the bone marrow (BM) microenvironment, acute myeloid leukemia (AML) cells constantly regulate their metabolic state based on extracellular signaling and nutrient availability by making "decisions," such as quiescence, proliferation, and differentiation. AML cells survive by meeting the biochemical demands of increased cell proliferation and continually adapting to changes in nutrient and oxygen availability. In addition, changes in the metabolism of amino acids, which are intermediate metabolites that fuel multiple biosynthetic pathways, as well as protein components, are another modality for meeting these demands. AML cells rewire metabolic pathways to adapt to increased nutritional demands for energy, reduced equivalents, and cell biosynthesis in the BM microenvironment. Furthermore, BM stromal cells and adipocytes play a role in preventing nutrient starvation-induced apoptosis of AML cells. Therefore, targeting metabolic abnormalities in AML cells is a promising novel therapeutic approach. Thus, this review describes the metabolic and molecular mechanisms of mitochondrial oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism in AML cells under the BM microenvironment.
    Keywords:  Acute myeloid leukemia; Bone marrow microenvironment; Energy metabolism
    DOI:  https://doi.org/10.11406/rinketsu.63.1046
  2. Front Cell Dev Biol. 2022 ;10 993915
    Lessons to cancer from studies of leukemia and hematopoiesis.
    Geoffrey Brown.
      The starting point to describing the origin and nature of any cancer must be knowledge about how the normal counterpart tissue develops. New principles to the nature of hematopoietic stem cells have arisen in recent years. In particular, hematopoietic stem cells can "choose" a cell lineage directly from a spectrum of the end-cell options, and are, therefore, a heterogeneous population of lineage affiliated/biased cells. These cells remain versatile because the developmental trajectories of hematopoietic stem and progenitor cells are broad. From studies of human acute myeloid leukemia, leukemia is also a hierarchy of maturing or partially maturing cells that are sustained by leukemia stem cells at the apex. This cellular hierarchy model has been extended to a wide variety of human solid tumors, by the identification of cancer stem cells, and is termed the cancer stem cell model. At least, two genomic insults are needed for cancer, as seen from studies of human childhood acute lymphoblastic leukemia. There are signature mutations for some leukemia's and some relate to a transcription factor that guides the cell lineage of developing hematopoietic stem/progenitor cells. Similarly, some oncogenes restrict the fate of leukemia stem cells and their offspring to a single maturation pathway. In this case, a loss of intrinsic stem cell versatility seems to be a property of leukemia stem cells. To provide more effective cures for leukemia, there is the need to find ways to eliminate leukemia stem cells.
    Keywords:  cancer stem cells; leukemia; leukemia stem cells; oncogenes; therapies
    DOI:  https://doi.org/10.3389/fcell.2022.993915
  3. Cell Rep. 2022 Oct 04. pii: S2211-1247(22)01286-4. [Epub ahead of print]41(1): 111445
    MCL-1 is a master regulator of cancer dependency on fatty acid oxidation.
    Michelle S Prew, Utsarga Adhikary, Dong Wook Choi, Erika P Portero, Joao A Paulo, Pruthvi Gowda, Amit Budhraja, Joseph T Opferman, Steven P Gygi, Nika N Danial, Loren D Walensky.
      MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors.
    Keywords:  BCL-2 family; CP: Cancer; CP: Metabolism; MCL-1; apoptosis; cancer; fatty acid oxidation; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2022.111445
  4. Front Oncol. 2022 ;12 1011191
    Differential glutamine metabolism in the tumor microenvironment - studies in diversity and heterogeneity: A mini-review.
    Michael D Claiborne, Robert Leone.
      Increased glutamine metabolism is a hallmark of many cancer types. In recent years, our understanding of the distinct and diverse metabolic pathways through which glutamine can be utilized has grown more refined. Additionally, the different metabolic requirements of the diverse array of cell types within the tumor microenvironment complicate the strategy of targeting any particular glutamine pathway as cancer therapy. In this Mini-Review, we discuss recent advances in further clarifying the cellular fate of glutamine through different metabolic pathways. We further discuss potential promising strategies which exploit the different requirements of cells in the tumor microenvironment as it pertains to glutamine metabolism in an attempt to suppress cancer growth and enhance anti-tumor immune responses.
    Keywords:  cancer; glutamine; immunooncology; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1011191
  5. Rinsho Ketsueki. 2022 ;63(9): 1052-1057
    [Novel therapies in AML and their resistance mechanisms].
    Koichi Takahashi.
      The landscape of acute myeloid leukemia treatment has changed dramatically over the past decade. In Japan, three novel molecularly targeted agents have been approved and rapidly changing the paradigm of AML therapy. However, as the clinical experience of these novel drugs accumulate, various resistance mechanisms have started to emerge. Here, we discuss the mechanism of action and resistance of the three recently approved drugs, FLT3 inhibitor, IDH inhibitor, and BCL2 inhibitor.
    Keywords:  Acute myeloid leukemia; Clonal heterogeneity; Drug resistance; Molecularly targeted agents
    DOI:  https://doi.org/10.11406/rinketsu.63.1052
  6. Biotechniques. 2022 Oct 07.
    Investigating myeloid cells? Go with the flow.
    Tristan Free.
      
    Keywords:  AML; Cancer; Drug sensitivity screening; Flow cytometry; Immunology; Leukemia; Myeloid cells
    DOI:  https://doi.org/10.2144/btn-2022-0099
  7. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2022 Oct;30(5): 1348-1353
    [Bone Marrow Osteoblasts Promotes the Proliferation Leukemia Stem Cell by Up-regulating Interleukin-1].
    Zhi-Jie Cao, Yi-Shuang Li, Hui-Jun Wang, Zhen-Ya Xue, Shu-Ying Chen, Ke-Jing Tang, Min Wang, Qing Rao.
       OBJECTIVE: To explore the extrinsic regulation mechanism of bone marrow microenvironment in leukemia cells, and investigate the promoting effect of osteoblast niche on the proliferation and self-renewal of leukemia stem cell by up-regulating the expression of interleukin-1 (IL-1) in leukemia cell.
    METHODS: The gene expression profiles on leukemia cells derived from AE9a mouse bone marrow endosteum and central bone marrow were determined by RNA sequencing and gene set enrichment analysis (GSEA). Quantitative real-time PCR (qRT-PCR) was used to detect the expression of IL-1 in AE9a mouse leukemia cells co-cultured with or without osteoblasts in vitro. In addition, qRT-PCR was also used to determine the expression of IL-1 in bone marrow mononuclear cell (BMMNC) from 43 patients with acute myeloid leukemia (AML). For leukemia cells co-cultured with osteoblasts or treated with IL-1β, colony forming ability of AE9a leukemia cells was determined by colony formation assay.
    RESULTS: In AE9a leukemia mouse, RNA-seq data and GSEA showed that the enrichment of the upregulated genes in leukemia cells located in endosteum fell into inflammatory response gene set, among them, IL-1α and IL-1β were significantly higher expressed in AE9a leukemia cells that located osteoblast niche (IL-1α: P<0.001, IL-1β:P<0.001). After AE9a leukemia cells were co-cultured with osteoblasts in vitro, the expression of IL-1α and IL-1β in leukemia cells were increased by 2.5 and 3.5 times respectively. In colony formation assay, the number of colonies was increased significantly after leukemia cells were co-cultured with osteoblasts (P<0.001). In addition, when AE9a leukemia cells were treated with IL-1β, the number of colonies was also increased significantly (P<0.01). In AML patients, BMMNC with high percentage of CD34 positive cells exhibited higher level of IL-1 expression.
    CONCLUSION: Osteoblast niche can promote leukemia cell proliferation and self-renewal through up-regulating the expression of IL-1 in leukemia cells. In AML patients, the expression level of IL-1 was correlated to the percentage of CD34 positive cells in BMMNC.
    Keywords:  interleukin-1 ; leukemia stem cells ; osteoblast niche
    DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2022.05.08
  8. Cytokine. 2022 Oct 03. pii: S1043-4666(22)00258-7. [Epub ahead of print]160 156049
    IL-7: Comprehensive review.
    Hila Winer, Gisele O L Rodrigues, Julie A Hixon, Francesca B Aiello, Tu Chun Hsu, Brianna T Wachter, Wenqing Li, Scott K Durum.
       OVERVIEW: IL-7 is a member of the family of cytokines with four anti-parallel α helixes that bind Type I cytokine receptors. It is produced by stromal cells and is required for development and homeostatic survival of lymphoid cells.
    GENOMIC ARCHITECTURE: Interleukin 7 (IL7) human IL7: gene ID: 3574 on ch 8; murine Il7 gene ID: 16,196 on ch 3.
    PROTEIN: Precursor contains a signal sequence, mature human IL-7 peptide 152aa, predicted 17.4kd peptide, glycosylated resulting in 25kd. Crystal structure: http://www.rcsb.org/structure/3DI2. REGULATION OF IL-7 PRODUCTION: Major producers are stromal cells in thymus, bone marrow and lymphoid organs but also reported in other tissues. Production is primarily constitutive but reported to be affected by IFNγ and other factors. IL-7 RECEPTORS: Two chains IL-7Rα (IL-7R) and γc (IL-2RG). Human IL-7R: gene ID 3575 on ch 5; human IL2RG: gene ID 3561 on ch X; mouse IL-7R: gene ID 16,197 on ch 15; murine Il2rg gene ID 16,186 on ch X. Member of γc family of receptors for cytokines IL-2, -4, -9, -15, and -21. Primarily expressed on lymphocytes but reports of other cell types. Expression in T-cells downregulated by IL-7. Low expression on Tregs, no expression on mature B-cells. Crystal structure: http://www.rcsb.org/structure/3DI2. IL-7 RECEPTOR SIGNAL TRANSDUCTION PATHWAYS: Major signals through JAK1, JAK3 to STAT5 and through non-canonical STAT3, STAT1, PI3K/AKT and MEK/ERK pathways. BIOLOGICAL ACTIVITY OF IL-7: Required for survival of immature thymocytes, naïve T-cells, memory T-cells, pro-B-cells and innate lymphocytes. Pharmacological treatment with IL-7 induces expansion of naïve and memory T-cells and pro-B-cells. ABNORMALITIES OF THE IL-7 PATHWAY IN DISEASE: Deficiencies in the IL-7 pathway in humans and mice result in severe combined immunodeficiency due to lymphopenia. Excessive signaling of the pathway in mice drives autoimmune diseases and in humans is associated with autoimmune syndromes including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, atopic dermatitis and asthma. Mutations in the IL-7 receptor pathway drive acute lymphoblastic leukemia.
    CLINICAL APPLICATIONS: IL-7 has been evaluated in patients with cancer and shown to expand lymphocytes. It accelerated lymphocyte recovery after hematopoietic stem cell transfer, and increased lymphocyte counts in AIDS patients and sepsis patients. Monoclonal antibodies blocking the IL-7 receptor are being evaluated in autoimmune diseases. Cytotoxic monoclonals are being evaluated in acute lymphoblastic leukemia. Drugs blocking the signal transduction pathway are being tested in autoimmunity and acute lymphoblastic leukemia.
    DOI:  https://doi.org/10.1016/j.cyto.2022.156049
  9. Cell Metab. 2022 Sep 28. pii: S1550-4131(22)00395-3. [Epub ahead of print]
    Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
    Erika Fernández-Vizarra, Sandra López-Calcerrada, Ana Sierra-Magro, Rafael Pérez-Pérez, Luke E Formosa, Daniella H Hock, María Illescas, Ana Peñas, Michele Brischigliaro, Shujing Ding, Ian M Fearnley, Charalampos Tzoulis, Robert D S Pitceathly, Joaquín Arenas, Miguel A Martín, David A Stroud, Massimo Zeviani, Michael T Ryan, Cristina Ugalde.
      The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, whereas the S-MRC preferentially maintains oxidative phosphorylation (OXPHOS) upon metabolic rewiring toward glycolysis. We show a link between the metabolic signatures converging at the PDC and the structural and functional organization of the MRC, challenging the widespread notion of the MRC as a single functional unit and concluding that its structural heterogeneity warrants optimal adaptation to metabolic function.
    Keywords:  COX7A1–2; SCAFI/COX7RP/COX7A2L; bioenergetics; glycolysis; metabolic switch; mitochondria; oxidative metabolism; pyruvate dehydrogenase; respiratory chain organizations; respiratory supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.005
  10. Curr Stem Cell Res Ther. 2022 Oct 03.
    Stem Cells: Therapeutic implications in chemotherapy and radiotherapy resistance in Cancer Therapy.
    Tejaswini Patil, Sonali S Rohiwal, Arpita P Tiwari.
      Cancer stem cells (CSCs) are transformed form of normal stem cells within heterogeneous mixture of cancer cells. These are mainly responsible for recurrence of cancer after treatment because of their ability to develop resistance against chemo and radiotherapy due to various factors such as, activation of signalling pathways important for self-renewal, DNA repair capacity, microenvironment and expression of ABC transporters. Targeting these mechanisms as potential factors can eliminate CSCs which eventually decreases cancer recurrence. This review focuses on the characteristics of CSCs, their role in development of resistance to chemotherapy and radiotherapy along with the therapeutic potential targets for successful elimination of CSC population.
    Keywords:  Cancer Stem cells; Cancer therapy; Chemotherapy; Drug resistance; Radiotherapy
    DOI:  https://doi.org/10.2174/1574888X17666221003125208
  11. Front Cell Dev Biol. 2022 ;10 1013885
    Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy.
    Chu Xiao, He Tian, Yujia Zheng, Zhenlin Yang, Shuofeng Li, Tao Fan, Jiachen Xu, Guangyu Bai, Jingjing Liu, Ziqin Deng, Chunxiang Li, Jie He.
      Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.
    Keywords:  TME; cancer metabolism; glycolysis; immunity regulation; immunotherapy
    DOI:  https://doi.org/10.3389/fcell.2022.1013885
  12. Oncoimmunology. 2022 ;11(1): 2127274
    Type I interferon induces cancer stem cells-mediated chemotherapy resistance.
    Mara De Martino, Claire Vanpouille-Box.
      In a recent study in Nature Immunology, Musella et al. demonstrate that suboptimal type I interferon (IFN-I) signaling in tumors undergoing immunogenic cell death (ICD) facilitates the accumulation of cancer stem cells (CSCs) by triggering the epigenetic regulator lysine demethylase 1B (KDM1B). KDM1B stands out as a promising target for the development of novel strategies to improve anti-cancer responses driven by ICD.
    Keywords:  Chemotherapy; KDM1B; cancer stem cells; epigenetic immune escape; immunogenic cell death; interferon type I
    DOI:  https://doi.org/10.1080/2162402X.2022.2127274
  13. Immunother Adv. 2022 ;2(1): ltac019
    Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.
    Stephanie Schwartz, Nidhi Patel, Tyler Longmire, Pushpa Jayaraman, Xiaomo Jiang, Hongbo Lu, Lisa Baker, Janelle Velez, Radha Ramesh, Anne-Sophie Wavreille, Melanie Verneret, Hong Fan, Tiancen Hu, Fangmin Xu, John Taraszka, Marc Pelletier, Joy Miyashiro, Mikael Rinne, Glenn Dranoff, Catherine Sabatos-Peyton, Viviana Cremasco.
       Objectives: Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab.
    Methods: Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed.
    Results: Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9.
    Conclusion: Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.
    DOI:  https://doi.org/10.1093/immadv/ltac019
  14. Front Cell Dev Biol. 2022 ;10 967461
    Editorial: Microenvironment-derived stem cell plasticity-volume II.
    Ivana Gadjanski, Slavko Mojsilovic, Marietta Herrmann, Jelena Krstic.
      
    Keywords:  3D culture; cancer stem cells; immunity; microenvironment; neural stem cells; plasticity; stem cell therapy
    DOI:  https://doi.org/10.3389/fcell.2022.967461
  15. Front Immunol. 2022 ;13 995785
    Biomarkers of related driver genes predict anti-tumor efficacy of immune checkpoint inhibitors.
    Shuai Jiang, Shuai Geng, Xinyu Luo, Can Zhang, Yang Yu, Mengfei Cheng, Shuo Zhang, Ning Shi, Mei Dong.
      Cancer is a disease with high morbidity and mortality in the world. In the past, the main treatment methods for cancer patients were surgery, radiotherapy and chemotherapy. However, with early treatment, the recurrence rate of cancer is higher, and the drug resistance of cancer cells is faster. In recent years, with the discovery of immune escape mechanism of cancer cells, Immunotherapy, especially Immune Checkpoint Inhibitors (ICIs), has made a breakthrough in the treatment of solid tumors, significantly prolonging the overall survival time and disease-free progression in some solid tumors, and its clinical benefits are more prominent than those of traditional anti-tumor drugs, which has become the hope of cancer patients after the failure of multi-line therapy. More and more studies have shown that there is a correlation between cancer driving genes and the clinical benefits of ICIs treatment, and the therapeutic effects and adverse reactions of ICIs can be predicted by the status of driving genes. Therefore, screening potential biomarkers of people who may benefit from immunotherapy in order to maximize the therapeutic benefits is a top priority. This review systematically summarizes the cancer driving genes that may affect the clinical benefits of immune checkpoint inhibitors, and provides accurate scientific basis for clinical practice.
    Keywords:  biomarker; cancer; immune checkpoint inhibitor; overall survival; progress free survival
    DOI:  https://doi.org/10.3389/fimmu.2022.995785
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