bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–03–05
thirteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Inhibition of adaptive therapy tolerance in cancer: is triplet mitochondrial targeting the key?
  2. Glutamine metabolism in breast cancer and possible therapeutic targets.
  3. What is cancer metabolism?
  4. Editorial: Targeting metabolism of cancer cells and host to overcome drug resistance: Preclinical and clinical studies.
  5. Editorial: Single cell meets metabolism and cancer biology.
  6. Mitochondrial gene expression signature predicts prognosis of pediatric acute myeloid leukemia patients.
  7. The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat.
  8. Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy.
  9. Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting.
  10. Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma.
  11. Bleb protrusions help cancer cells to cheat death.
  12. Protocol for isolation and analysis of the leukemia stem cells in BCR-ABL-driven chronic myelogenous leukemia mice.
  13. Mechanism of action of lactic acid on histones in cancer.
  1. Mol Oncol. 2023 Feb 28.
    Inhibition of adaptive therapy tolerance in cancer: is triplet mitochondrial targeting the key?
    Jukka Westermarck.
      Targeted therapies have become a mainstay in the treatment of cancer, but their long-term efficacy is compromised by acquired drug resistance. Acquired therapy resistance develops via two phases - first through adaptive development of non-genetic drug tolerance which is followed by stable resistance through acquisition of genetic mutations. Drug tolerance has been described in practically all clinical cancer treatment contexts, and detectable drug-tolerant tumors are highly associated with treatment relapse and poor survival. Thereby novel therapeutic strategies are needed to overcome cancer therapy tolerance. Recent studies have identified a critical role of mitochondrial mechanisms in defining cancer cell sensitivity to targeted therapies and the surprising effects of established cancer therapies on mitochondria. Here, these recent studies are reviewed emphasizing an emerging concept of triplet therapies including three compounds targeting different cancer cell vulnerabilities, but including at least one compound that targets the mitochondria. These mitochondria-targeting triplet therapies have very promising preclinical effects in overcoming cancer therapy tolerance. Potential strategies of how to overcome challenges in clinical translation of mitochondria targeting triplet therapies are also discussed.
    Keywords:  BH3; Oxidative phosphorylation; Protein phosphatase 2A; Pyruvate dehydrogenase; acute myeloid leukemia; glioblastoma
    DOI:  https://doi.org/10.1002/1878-0261.13406
  2. Biochem Pharmacol. 2023 Feb 25. pii: S0006-2952(23)00055-2. [Epub ahead of print] 115464
    Glutamine metabolism in breast cancer and possible therapeutic targets.
    Shiqi Li, Hui Zeng, Junli Fan, Fubing Wang, Chen Xu, Yirong Li, Jiancheng Tu, Kenneth P Nephew, Xinghua Long.
      Cancer is characterized by metabolic reprogramming, which is a hot topic in tumor treatment research. Cancer cells alter metabolic pathways to promote their growth, and the common purpose of these altered metabolic pathways is to adapt the metabolic state to the uncontrolled proliferation of cancer cells. Most cancer cells in a state of nonhypoxia will increase the uptake of glucose and produce lactate, called the Warburg effect. Increased glucose consumption is used as a carbon source to support cell proliferation, including nucleotide, lipid and protein synthesis. In the Warburg effect, pyruvate dehydrogenase activity decreases, thereby disrupting the TCA cycle. In addition to glucose, glutamine is also an important nutrient for the growth and proliferation of cancer cells, an important carbon bank and nitrogen bank for the growth and proliferation of cancer cells, providing ribose, nonessential amino acids, citrate, and glycerin necessary for cancer cell growth and proliferation and compensating for the reduction in oxidative phosphorylation pathways in cancer cells caused by the Warburg effect. In human plasma, glutamine is the most abundant amino acid. Normal cells produce glutamine via glutamine synthase (GLS), but the glutamine synthesized by tumor cells is insufficient to meet their high growth needs, resulting in a "glutamine-dependent phenomenon." Most cancers have an increased glutamine demand, including breast cancer. Metabolic reprogramming not only enables tumor cells to maintain the reduction-oxidation (redox) balance and commit resources to biosynthesis but also establishes heterogeneous metabolic phenotypes of tumor cells that are distinct from those of nontumor cells. Thus, targeting the metabolic differences between tumor and nontumor cells may be a promising and novel anticancer strategy. Glutamine metabolic compartments have emerged as promising candidates, especially in TNBC and drug-resistant breast cancer. In this review, the latest discoveries of breast cancer and glutamine metabolism are discussed, novel treatment methods based on amino acid transporters and glutaminase are discussed, and the relationship between glutamine metabolism and breast cancer metastasis, drug resistance, tumor immunity and ferroptosis are explained, which provides new ideas for the clinical treatment of breast cancer.
    Keywords:  Amino acid transporters; Breast cancer; Glutaminase; Glutamine metabolism; Immune microenvironment; ferroptosis
    DOI:  https://doi.org/10.1016/j.bcp.2023.115464
  3. Cell. 2023 Feb 22. pii: S0092-8674(23)00097-1. [Epub ahead of print]
    What is cancer metabolism?
    Lydia W S Finley.
      The uptake and metabolism of nutrients support fundamental cellular process from bioenergetics to biomass production and cell fate regulation. While many studies of cell metabolism focus on cancer cells, the principles of metabolism elucidated in cancer cells apply to a wide range of mammalian cells. The goal of this review is to discuss how the field of cancer metabolism provides a framework for revealing principles of cell metabolism and for dissecting the metabolic networks that allow cells to meet their specific demands. Understanding context-specific metabolic preferences and liabilities will unlock new approaches to target cancer cells to improve patient care.
    DOI:  https://doi.org/10.1016/j.cell.2023.01.038
  4. Front Oncol. 2023 ;13 1154661
    Editorial: Targeting metabolism of cancer cells and host to overcome drug resistance: Preclinical and clinical studies.
    Lishun Wang, Hanchen Xu, Yadi Wu.
      
    Keywords:  cancer metabolism; drug resistance; gut microbiome; metabolite; omics
    DOI:  https://doi.org/10.3389/fonc.2023.1154661
  5. Front Oncol. 2023 ;13 1125186
    Editorial: Single cell meets metabolism and cancer biology.
    Jieqiong Wang, Shibiao Wan.
      
    Keywords:  bioinformatics; cancer biology; computational biology; machine learning; metabolism; single cell analysis
    DOI:  https://doi.org/10.3389/fonc.2023.1125186
  6. Front Oncol. 2023 ;13 1109518
    Mitochondrial gene expression signature predicts prognosis of pediatric acute myeloid leukemia patients.
    Shilpi Chaudhary, Shuvadeep Ganguly, Jayanth Kumar Palanichamy, Archna Singh, Dibyabhaba Pradhan, Radhika Bakhshi, Anita Chopra, Sameer Bakhshi.
       Introduction: Gene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance.
    Methods: Children with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset.
    Results: In 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrell's c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset.
    Discussion: We identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.
    Keywords:  RNA sequencing; acute myeloid leukema; child; gene signature; mitochondria
    DOI:  https://doi.org/10.3389/fonc.2023.1109518
  7. Mitochondrion. 2023 Feb 28. pii: S1567-7249(23)00016-8. [Epub ahead of print]
    The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat.
    Peter W Stacpoole, Charles E McCall.
      Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.
    Keywords:  Aerobic glycolysis; Aging; Cancer; Diabetes; Embryogenesis; Inflammation; Neurodegeneration; Oxidative phosphorylation; Pyruvate dehydrogenase complex; Sepsis
    DOI:  https://doi.org/10.1016/j.mito.2023.02.007
  8. Biochim Biophys Acta Rev Cancer. 2023 Feb 24. pii: S0304-419X(23)00015-X. [Epub ahead of print] 188866
    Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy.
    Jing Ye, Junhao Wu, Bo Liu.
      Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated of cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.
    Keywords:  Cancer therapy; DNA damage repair; Deregulated of cell death; Drug resistance; Dual-target small molecule; Enhanced drug efflux; Epigenetic alteration; Therapeutic strategy
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188866
  9. J Hematol Oncol. 2023 Mar 03. 16(1): 17
    Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting.
    Katherine W DiNardo, Thomas W LeBlanc, Hui Chen.
      Developments in investigational agents and novel regimens in acute myeloid leukemia (AML) were reported in the 2022 American Society of Hematology (ASH) annual meeting. Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody-drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.
    Keywords:  AML; Acute myeloid leukemia; Clinical research; Investigational therapies
    DOI:  https://doi.org/10.1186/s13045-023-01411-x
  10. bioRxiv. 2023 Feb 22. pii: 2023.02.22.529457. [Epub ahead of print]
    Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma.
    Natthakan Thongon, Feiyang Ma, Pamela Lockyer, Natalia Baran, Jintan Liu, Christopher Jackson, Ashley Rose, Bethany Wildeman, Matteo Marchesini, Valentina Marchica, Paola Storti, Nicola Giuliani, Irene Ganan-Gomez, Vera Adema, Yun Qing, Min Ha, Rodrigo Fonseca, Caleb Class, Lin Tan, Rashmi Kanagal-Shamanna, David Berrios Nolasco, Claudio Cerchione, Guillermo Montalban-Bravo, Andrea Santoni, Carlos Bueso-Ramos, Marina Konopleva, Philip Lorenzi, Guillermo Garcia-Manero, Elisabeth Manasanch, Andrea Viale, Marta Chesi, Simona Colla.
      DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration. Our study revealed a novel vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.
    STATEMENT OF SIGNIFICANCE: Metabolic reprogramming is a mechanism through which cancer cells maintain survival and become resistant to DNA-damaging therapy. Here, we show that targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.
    DOI:  https://doi.org/10.1101/2023.02.22.529457
  11. Nature. 2023 Mar 01.
    Bleb protrusions help cancer cells to cheat death.
    Michal Reichman-Fried, Erez Raz.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-023-00477-4
  12. STAR Protoc. 2023 Feb 14. pii: S2666-1667(23)00081-3. [Epub ahead of print]4(1): 102123
    Protocol for isolation and analysis of the leukemia stem cells in BCR-ABL-driven chronic myelogenous leukemia mice.
    Chang Liu, Xiaoying Lin, Yanli Jin, Jingxuan Pan.
      Practical procedures for sorting and analysis of leukemia stem cells (LSCs) are to improve our understanding of chronic myelogenous leukemia (CML). Here, we present a detailed magnetic-bead-based sorting and flow-cytometry-based analysis protocol for LSCs in BCR-ABL-driven CML mice. We describe steps for sorting and functional analysis of BCR-ABL-expressing c-Kit+ cells (GFP+c-Kit+) from CML mice as well as antibody staining and gating strategies for characterization of leukemia stem/progenitor cells and myeloid leukemia cells. For complete details on the use and execution of this protocol, please refer to Liu et al. (2022).1.
    Keywords:  Cell isolation; Flow Cytometry/Mass Cytometry; Model Organisms; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2023.102123
  13. Antioxid Redox Signal. 2023 Feb 27.
    Mechanism of action of lactic acid on histones in cancer.
    Riccardo Sgarra, Sabrina Battista, Laura Cerchia, Guidalberto Manfioletti, Monica Fedele.
       SIGNIFICANCE: Metabolic end products and intermediates can exert signaling functions as chemical sources for histone post-translational modifications, which remodel chromatin and affect gene expression. Among them, lactic acid is responsible for histone lactylation, a recently discovered histone mark that occurs in high lactate conditions, such as those resulting from the Warburg effect in cancer cells.
    RECENT ADVANCES: Late-breaking studies have advanced the knowledge on the mechanisms involved in histone lactylation, requiring independent non-enzyme-dependent and enzyme-dependent reactions, which is emerging as an important hallmark of cancer cells linking metabolic changes to gene expression reprogramming.
    CRITICAL ISSUES: Here, we give an overview about this new epigenetic modification, focusing on its mechanism of action in tumors and tumor microenvironment.
    FUTURE DIRECTIONS: Further investigation on the competition mechanism between lactylation and acetylation, as well as on the mechanisms by which lactate fluctuation can control a specific gene set in a given tissue are needed in the coming years to exploit new anti-cancer therapeutic approaches.
    DOI:  https://doi.org/10.1089/ars.2022.0190
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