bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–04–16
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Editorial: Reviews in cancer metabolism.
  2. Targeting cancer metabolic vulnerabilities for advanced therapeutic efficacy.
  3. High Throughput Fluorescence-Based In Vitro Experimental Platform for the Identification of Effective Therapies to Overcome Tumour Microenvironment-Mediated Drug Resistance in AML.
  4. Crosstalk between oxidative phosphorylation and immune escape in cancer: a new concept of therapeutic targets selection.
  5. Mitochondrial CPT1A: Insights into structure, function, and basis for drug development.
  6. Oncogenic drivers dictate immune control of acute myeloid leukemia.
  7. Novel strategies for cancer immunotherapy: counter-immunoediting therapy.
  8. Overcoming drug resistance in cancer.
  9. Dynamics of Epithelial-Mesenchymal Plasticity: What Have Single-Cell Investigations Elucidated So Far?
  10. Therapeutic targeting of ACLY in T-ALL in vivo.
  11. Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience.
  12. In vitro simulation of the acute lymphoblastic leukemia niche: a critical view on the optimal approximation for drug testing.
  1. Front Oncol. 2023 ;13 1167484
    Editorial: Reviews in cancer metabolism.
    Nadia Jacobo-Herrera, Bela Ozsvari.
      
    Keywords:  cancer metabolism; metabolic reprogramming; metabolic therapy; mitochondria; resistance mechanisms
    DOI:  https://doi.org/10.3389/fonc.2023.1167484
  2. Biomed Pharmacother. 2023 Apr 07. pii: S0753-3322(23)00446-8. [Epub ahead of print]162 114658
    Targeting cancer metabolic vulnerabilities for advanced therapeutic efficacy.
    Tobias Achu Muluh, Xing-Sheng Shu, Ying Ying.
      Cancer metabolism is how cancer cells utilize nutrients and energy to support their growth and proliferation. Unlike normal cells, cancer cells have a unique metabolic profile that allows them to generate energy and the building blocks they need for rapid growth and division. This metabolic profile is marked by an increased reliance on glucose and glutamine as energy sources and changes in how cancer cells use and make key metabolic intermediates like ATP, NADH, and NADPH. This script analyzes a comprehensive overview of the latest advances in tumor metabolism, identifying the key unresolved issues, elaborates on how tumor cells differ from normal cells in their metabolism of nutrients, and explains how tumor cells conflate growth signals and nutrients to proliferate. The metabolic interaction of tumorigenesis and lipid metabolism within the tumor microenvironment and the role of ROS as an anti-tumor agent by mediating various signaling pathways for clinical cancer therapeutic targeting are outlined. Cancer metabolism is highly dynamic and heterogeneous; thus, advanced technologies to better investigate metabolism at the unicellular level without altering tumor tissue are necessary for better research and clinical transformation. The study of cancer metabolism is an area of active research, as scientists seek to understand the underlying metabolic changes that drive cancer growth and to identify potential therapeutic targets.
    Keywords:  Cancer metabolism; Lipid metabolism; Metabolic reprogramming and Pathways; Reactive oxygen species; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2023.114658
  3. Cancers (Basel). 2023 Mar 27. pii: 1988. [Epub ahead of print]15(7):
    High Throughput Fluorescence-Based In Vitro Experimental Platform for the Identification of Effective Therapies to Overcome Tumour Microenvironment-Mediated Drug Resistance in AML.
    Yoana Arroyo-Berdugo, Maria Sendino, David Greaves, Natalia Nojszewska, Orest Idilli, Chi Wai So, Lucy Di Silvio, Ruby Quartey-Papafio, Farzin Farzaneh, Jose Antonio Rodriguez, Yolanda Calle.
      The interactions between Acute Myeloid Leukaemia (AML) leukemic stem cells and the bone marrow (BM) microenvironment play a critical role during AML progression and resistance to drug treatments. Therefore, the identification of novel therapies requires drug-screening methods using in vitro co-culture models that closely recreate the cytoprotective BM setting. We have developed a new fluorescence-based in vitro co-culture system scalable to high throughput for measuring the concomitant effect of drugs on AML cells and the cytoprotective BM microenvironment. eGFP-expressing AML cells are co-cultured in direct contact with mCherry-expressing BM stromal cells for the accurate assessment of proliferation, viability, and signaling in both cell types. This model identified several efficacious compounds that overcome BM stroma-mediated drug resistance against daunorubicin, including the chromosome region maintenance 1 (CRM1/XPO1) inhibitor KPT-330. In silico analysis of genes co-expressed with CRM1, combined with in vitro experiments using our new methodology, also indicates that the combination of KPT-330 with the AURKA pharmacological inhibitor alisertib circumvents the cytoprotection of AML cells mediated by the BM stroma. This new experimental model and analysis provide a more precise screening method for developing improved therapeutics targeting AML cells within the cytoprotective BM microenvironment.
    Keywords:  AML; KPT-330; co-culture system; daunorubicin; resistance; selinexor; tumour microenvironment
    DOI:  https://doi.org/10.3390/cancers15071988
  4. Cell Oncol (Dordr). 2023 Apr 11.
    Crosstalk between oxidative phosphorylation and immune escape in cancer: a new concept of therapeutic targets selection.
    Xutong Qiu, Yi Li, Zhuoyuan Zhang.
       BACKGROUND: Cancer is increasingly recognized as a metabolic disease, with evidence suggesting that oxidative phosphorylation (OXPHOS) plays a significant role in the progression of numerous cancer cells. OXPHOS not only provides sufficient energy for tumor tissue survival but also regulates conditions for tumor proliferation, invasion, and metastasis. Alterations in OXPHOS can also impair the immune function of immune cells in the tumor microenvironment, leading to immune evasion. Therefore, investigating the relationship between OXPHOS and immune escape is crucial in cancer-related research. This review aims to summarize the effects of transcriptional, mitochondrial genetic, metabolic regulation, and mitochondrial dynamics on OXPHOS in different cancers. Additionally, it highlights the role of OXPHOS in immune escape by affecting various immune cells. Finally, it concludes with an overview of recent advances in antitumor strategies targeting both immune and metabolic processes and proposes promising therapeutic targets by analyzing the limitations of current targeted drugs.
    CONCLUSIONS: The metabolic shift towards OXPHOS contributes significantly to tumor proliferation, progression, metastasis, immune escape, and poor prognosis. A thorough investigation of concrete mechanisms of OXPHOS regulation in different types of tumors and the combination usage of OXPHOS-targeted drugs with existing immunotherapies could potentially uncover new therapeutic targets for future antitumor therapies.
    Keywords:  Cancer therapy; Immunotherapy; Metabolism; OXPHOS
    DOI:  https://doi.org/10.1007/s13402-023-00801-0
  5. Front Pharmacol. 2023 ;14 1160440
    Mitochondrial CPT1A: Insights into structure, function, and basis for drug development.
    Kai Liang.
      Carnitine Palmitoyl-Transferase1A (CPT1A) is the rate-limiting enzyme in the fatty acid β-oxidation, and its deficiency or abnormal regulation can result in diseases like metabolic disorders and various cancers. Therefore, CPT1A is a desirable drug target for clinical therapy. The deep comprehension of human CPT1A is crucial for developing the therapeutic inhibitors like Etomoxir. CPT1A is an appealing druggable target for cancer therapies since it is essential for the survival, proliferation, and drug resistance of cancer cells. It will help to lower the risk of cancer recurrence and metastasis, reduce mortality, and offer prospective therapy options for clinical treatment if the effects of CPT1A on the lipid metabolism of cancer cells are inhibited. Targeted inhibition of CPT1A can be developed as an effective treatment strategy for cancers from a metabolic perspective. However, the pathogenic mechanism and recent progress of CPT1A in diseases have not been systematically summarized. Here we discuss the functions of CPT1A in health and diseases, and prospective therapies targeting CPT1A. This review summarizes the current knowledge of CPT1A, hoping to prompt further understanding of it, and provide foundation for CPT1A-targeting drug development.
    Keywords:  CPT1a; FATTY ACID β-OXIDATION; cancer; drug development; inhibitor
    DOI:  https://doi.org/10.3389/fphar.2023.1160440
  6. Nat Commun. 2023 Apr 14. 14(1): 2155
    Oncogenic drivers dictate immune control of acute myeloid leukemia.
    Rebecca J Austin, Jasmin Straube, Rohit Halder, Yashaswini Janardhanan, Claudia Bruedigam, Matthew Witkowski, Leanne Cooper, Amy Porter, Matthias Braun, Fernando Souza-Fonseca-Guimaraes, Simone A Minnie, Emily Cooper, Sebastien Jacquelin, Axia Song, Tobias Bald, Kyohei Nakamura, Geoffrey R Hill, Iannis Aifantis, Steven W Lane, Megan J Bywater.
      Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.
    DOI:  https://doi.org/10.1038/s41467-023-37592-9
  7. J Hematol Oncol. 2023 Apr 13. 16(1): 38
    Novel strategies for cancer immunotherapy: counter-immunoediting therapy.
    Shaochuan Liu, Qian Sun, Xiubao Ren.
      The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer.
    DOI:  https://doi.org/10.1186/s13045-023-01430-8
  8. Cell. 2023 Apr 13. pii: S0092-8674(23)00282-9. [Epub ahead of print]186(8): 1515-1516
    Overcoming drug resistance in cancer.
    Jerry C Madukwe.
      
    DOI:  https://doi.org/10.1016/j.cell.2023.03.019
  9. ACS Omega. 2023 Apr 04. 8(13): 11665-11673
    Dynamics of Epithelial-Mesenchymal Plasticity: What Have Single-Cell Investigations Elucidated So Far?
    Seemadri Subhadarshini, Joel Markus, Sarthak Sahoo, Mohit Kumar Jolly.
      Epithelial-mesenchymal plasticity (EMP) is a key driver of cancer metastasis and therapeutic resistance, through which cancer cells can reversibly and dynamically alter their molecular and functional traits along the epithelial-mesenchymal spectrum. While cells in the epithelial phenotype are usually tightly adherent, less metastatic, and drug-sensitive, those in the hybrid epithelial/mesenchymal and/or mesenchymal state are more invasive, migratory, drug-resistant, and immune-evasive. Single-cell studies have emerged as a powerful tool in gaining new insights into the dynamics of EMP across various cancer types. Here, we review many recent studies that employ single-cell analysis techniques to better understand the dynamics of EMP in cancer both in vitro and in vivo. These single-cell studies have underlined the plurality of trajectories cells can traverse during EMP and the consequent heterogeneity of hybrid epithelial/mesenchymal phenotypes seen at both preclinical and clinical levels. They also demonstrate how diverse EMP trajectories may exhibit hysteretic behavior and how the rate of such cell-state transitions depends on the genetic/epigenetic background of recipient cells, as well as the dose and/or duration of EMP-inducing growth factors. Finally, we discuss the relationship between EMP and patient survival across many cancer types. We also present a next set of questions related to EMP that could benefit much from single-cell observations and pave the way to better tackle phenotypic switching and heterogeneity in clinic.
    DOI:  https://doi.org/10.1021/acsomega.2c07989
  10. bioRxiv. 2023 Mar 28. pii: 2023.03.27.534395. [Epub ahead of print]
    Therapeutic targeting of ACLY in T-ALL in vivo.
    Victoria da Silva-Diz, Amartya Singh, Olga Lancho, Maya Aleksandrova, Komal Mandleywala, Patricia Renck Nunes, Jesminara Khatun, Oekyung Kim, Eric Chiles, Xiaoyang Su, Hossein Khiabanian, Kathryn E Wellen, Daniel Herranz.
      T-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as a novel therapeutic target in T-ALL. Our results show that ACLY is overexpressed in T-ALL, and its expression correlates with NOTCH1 activity. To test the effects of ACLY in leukemia progression and the response to NOTCH1 inhibition, we developed an isogenic model of NOTCH1-induced Acly conditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibition in vivo . Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of NOTCH1 inhibition in vivo , with significantly downregulated pathways related to oxidative phosphorylation, electron transport chain, ribosomal biogenesis and nucleosome biology. Consistently, metabolomic profiling upon ACLY loss revealed a metabolic crisis with accumulation of nucleotide intermediates and reduced levels of several amino acids. Overall, our results identify a link between NOTCH1 and ACLY and unveil ACLY as a novel promising target for T-ALL treatment.
    DOI:  https://doi.org/10.1101/2023.03.27.534395
  11. Cancers (Basel). 2023 Mar 26. pii: 1983. [Epub ahead of print]15(7):
    Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience.
    Adriana Trabal, Amber Gibson, Jiasen He, David McCall, Michael Roth, Cesar Nuñez, Miriam Garcia, Meredith Buzbee, Laurie Toepfer, Aram Bidikian, Naval Daver, Tapan Kadia, Nicholas J Short, Ghayas C Issa, Farhad Ravandi, Courtney D DiNardo, Guillermo Montalban Bravo, Sofia Garces, Andrea Marcogliese, Hana Paek, Zoann Dreyer, Julienne Brackett, Michele Redell, Joanna Yi, Guillermo Garcia-Manero, Marina Konopleva, Alexandra Stevens, Branko Cuglievan.
      The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions' experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6-21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.
    Keywords:  Bcl-2 inhibitor; acute myeloid leukemia; children; pediatric; venetoclax
    DOI:  https://doi.org/10.3390/cancers15071983
  12. J Leukoc Biol. 2023 Apr 11. pii: qiad039. [Epub ahead of print]
    In vitro simulation of the acute lymphoblastic leukemia niche: a critical view on the optimal approximation for drug testing.
    Igor Pottosin, Miguel Olivas-Aguirre, Oxana Dobrovinskaya.
      Acute lymphoblastic leukemia (ALL) with the worst prognosis is related to minimal residual disease, MRD. MRD not only depends on the individual peculiarities of leukemic clones but also reflects the protective role of the ALL microenvironment. In this review we discuss in detail cell-to-cell interactions in the two leukemic niches, more explored bone marrow (BM) and less studied extramedullary adipose tissue (EMAT). A special emphasis is given to multiple ways of interactions of ALL cells with BM or EMAT microenvironment, indicating observed differences in B- and T-ALL behavior. This analysis argued for the usage of co-culture systems for drug testing. Starting with a review of available sources and characteristics of ALL cells, mesenchymal stromal cells (MSC), endothelial cells and adipocytes, we have then made an update of the available 2D and 3D systems, which bring together cellular elements, components of the extracellular matrix (ECM) or its imitation. We discussed the most complex available 3D systems like "leukemia-on-a-chip", which include either a prefabricated microfluidics platform or, alternatively, the microarchitecture, designed by using the 3D bioprinting technologies. From our analysis it follows that for preclinical antileukemic drug testing in most cases intermediately complex in vitro cell systems are optimal, such as a "2.5D" co-culture of ALL cells with niche cells (MSC, endothelial cells) plus matrix components or scaffold-free MSC organoids, populated by ALL cells. Due to emerging evidence for the correlation of obesity and poor prognosis, a co-culture of adipocytes with ALL cells as a drug testing system is gaining shape.
    Keywords:  ALL cell lines; acute lymphoblastic leukemia; adipose tissue; bone marrow; co-culture; leukemic niche; mesenchymal stromal cells
    DOI:  https://doi.org/10.1093/jleuko/qiad039
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