bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–01–22
fourteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. TIM3, a human acute myeloid leukemia stem cell marker, does not enrich for leukemia-initiating stem cells in B-cell acute lymphoblastic leukemia.
  2. Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.
  3. A Trifunctional Natural Killer Cell Engager Can Target CD123+ Leukemia.
  4. The Role of Immune Checkpoint Inhibitors in Cancer Therapy.
  5. Dexamethasone-Induced Fatty Acid Oxidation and Autophagy/Mitophagy Are Essential for T-ALL Glucocorticoid Resistance.
  6. Acetyl-CoA metabolism in cancer.
  7. Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment.
  8. Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.
  9. Cancer Stem Cells are Actually Stem Cells with Disordered Differentiation: the Monophyletic Origin of Cancer.
  10. The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited.
  11. Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.
  12. The Successful Implementation of a Modified Pediatric Acute Lymphoblastic Leukemia Protocol to Treat an Elderly Patient With T-cell Lymphoblastic Leukemia: A Case Report.
  13. Prognostic Role of CD200 in Acute Lymphoblastic Leukemia Patients.
  14. Are There Specific Cancer Stem Cell Markers?
  1. Haematologica. 2023 Jan 19.
    TIM3, a human acute myeloid leukemia stem cell marker, does not enrich for leukemia-initiating stem cells in B-cell acute lymphoblastic leukemia.
    Clara Bueno, Alba Martínez, Paola Alejandra Romecin, Samanta Romina Zanetti, Ricky Tirtakusuma, Eulalia Genesca, Mireia Camós, Manuel Ramírez-Orellana, Eduardo Anguita, Paola Ballerini, Franco Locatelli, José Luis Fuster, Pablo Menéndez.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.282394
  2. Cancers (Basel). 2023 Jan 12. pii: 484. [Epub ahead of print]15(2):
    Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.
    Rebecca Anderson, Kristin M Pladna, Nathaniel J Schramm, Frances B Wheeler, Steven Kridel, Timothy S Pardee.
      Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML.
    Keywords:  leukemia; metabolism; mitochondria; therapy
    DOI:  https://doi.org/10.3390/cancers15020484
  3. Cancer Discov. 2023 Jan 20. OF1
    A Trifunctional Natural Killer Cell Engager Can Target CD123+ Leukemia.
      A trifunctional natural killer cell engager (NKCE) kills CD123+ acute myeloid leukemia (AML) blasts.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-011
  4. Clin Pract. 2022 Dec 27. 13(1): 22-40
    The Role of Immune Checkpoint Inhibitors in Cancer Therapy.
    Ahmed M Basudan.
      Over the years, immune checkpoint inhibitors (CPIs) have become a powerful treatment strategy in the field of cancer immunotherapy. In the last decade, the number of FDA-approved CPIs has been increasing prominently, opening new horizons for the treatment of a wide range of tumor types. Pointedly, three immune checkpoint molecules have been under extensive research, which include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand-1 (PD-L1). Despite remarkable success, not all patients respond positively to therapy, which highlights the complexity of the tumor microenvironment (TME) and immune system. This has led to the identification of molecular biomarkers to predict response and toxicity. In addition, there has been an emerging focus on developing new delivery and targeting approaches for better drug efficacy and potency. In this review, we highlight the mechanism of action of major CPIs, their clinical impact, variation in effectiveness, response prediction, updated clinical indications, current challenges and limitations, promising novel approaches, and future directions.
    Keywords:  CTLA-4; PD-1; PD-L1; cancer; checkpoint inhibitors; immunotherapy
    DOI:  https://doi.org/10.3390/clinpract13010003
  5. Cancers (Basel). 2023 Jan 10. pii: 445. [Epub ahead of print]15(2):
    Dexamethasone-Induced Fatty Acid Oxidation and Autophagy/Mitophagy Are Essential for T-ALL Glucocorticoid Resistance.
    Miguel Olivas-Aguirre, Jesús Pérez-Chávez, Liliana Torres-López, Arturo Hernández-Cruz, Igor Pottosin, Oxana Dobrovinskaya.
      ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study analyzed the effects of Dex, one of the main GCs used in ALL treatment, on two T-ALL cell lines: resistant Jurkat and unselected CCRF-CEM, representing a mixture of sensitive and resistant clones. In addition to nuclear targeting, we observed a massive accumulation of Dex in mitochondria. Dex-treated leukemic cells suffered metabolic reprogramming from glycolysis and glutaminolysis towards lipolysis and increased FAO, along with increased membrane polarization and ROS production. Dex provoked mitochondrial fragmentation and induced autophagy/mitophagy. Mitophagy preceded cell death in susceptible populations of CCRF-CEM cells while serving as a pro-survival mechanism in resistant Jurkat. Accordingly, preventing FAO or autophagy greatly increased the Dex cytotoxicity and overcame GC resistance. Dex acted synergistically with mitochondria-targeted drugs, curcumin, and cannabidiol. Collectively, our data suggest that GCs treatment should not be neglected even in apparently GC-resistant clinical cases. Co-administration of drugs targeting mitochondria, FAO, or autophagy can help to overcome GC resistance.
    Keywords:  acute lymphoblastic leukemia; autophagy; dexamethasone; glucocorticoid resistance; glucocorticoids; leukemic microenvironment; metabolic reprogramming; mitophagy
    DOI:  https://doi.org/10.3390/cancers15020445
  6. Nat Rev Cancer. 2023 Jan 19.
    Acetyl-CoA metabolism in cancer.
    David A Guertin, Kathryn E Wellen.
      Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.
    DOI:  https://doi.org/10.1038/s41568-022-00543-5
  7. Biomedicines. 2023 Jan 11. pii: 189. [Epub ahead of print]11(1):
    Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment.
    Ferenc Sipos, Györgyi Műzes.
      Inflammatory processes and cancer stem cells (CSCs) are increasingly recognized as factors in the development of tumors. Emerging evidence indicates that CSCs are associated with cancer properties such as metastasis, treatment resistance, and disease recurrence. However, the precise interaction between CSCs and the immune microenvironment remains unexplored. Although evasion of the immune system by CSCs has been extensively studied, new research demonstrates that CSCs can also control and even profit from the immune response. This review provides an overview of the reciprocal interplay between CSCs and tumor-infiltrating immune cells, collecting pertinent data about how CSCs stimulate leukocyte reprogramming, resulting in pro-tumor immune cells that promote metastasis, chemoresistance, tumorigenicity, and even a rise in the number of CSCs. Tumor-associated macrophages, neutrophils, Th17 and regulatory T cells, mesenchymal stem cells, and cancer-associated fibroblasts, as well as the signaling pathways involved in these pro-tumor activities, are among the immune cells studied. Although cytotoxic leukocytes have the potential to eliminate CSCs, immune evasion mechanisms in CSCs and their clinical implications are also known. We intended to compile experimental findings that provide direct evidence of interactions between CSCs and the immune system and CSCs and the inflammatory milieu. In addition, we aimed to summarize key concepts in order to comprehend the cross-talk between CSCs and the tumor microenvironment as a crucial process for the effective design of anti-CSC therapies.
    Keywords:  cancer stem cells; cancer-associated fibroblasts; inflammation; leukocyte reprogramming; regulatory T cells; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/biomedicines11010189
  8. Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2208176120
    Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.
    Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, François Lemonnier, Wanda Y Li, Miki S Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M Robinson, Annick You-Ten, Daniel J Butler, Thorsten Berger, Mark D Minden, Ross L Levine, Cynthia J Guidos, Ari M Melnick, Christopher E Mason, Tak W Mak.
      Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.
    Keywords:  IDH; TET2; epigenetics; myeloid neoplasm
    DOI:  https://doi.org/10.1073/pnas.2208176120
  9. Stem Cell Rev Rep. 2023 Jan 17.
    Cancer Stem Cells are Actually Stem Cells with Disordered Differentiation: the Monophyletic Origin of Cancer.
    Qiankun Luo, Pan Liu, Pengfei Yu, Tao Qin.
      Cancer stem cells (CSCs) play an important role in cancer development. Based on advancements in CSC research, we propose a monophyletic model of cancer. This model is based on the idea that CSCs are stem cells with disordered differentiation whose original purpose was to repair damaged tissues. Inflammatory responses and damage repair signals are crucial for the creation and maintenance of CSCs. Normal quiescent stem cells are activated by environmental stimulation, such as an inflammatory response, and undergo cell division and differentiation. In the initial stage of cancer development, stem cell differentiation leads to heteromorphism due to the accumulation of gene mutations, resulting in the development of metaplasia or precancerosis. In the second stage, accumulated mutations induce poor differentiation and lead to cancer development. The monophyletic model illustrates the evolution, biological behavior, and hallmarks of CSCs, proposes a concise understanding of the origin of cancer, and may encourage a novel therapeutic approach.
    Keywords:  Cancer stem cells; Differentiation; Inflammatory response; Tissue repair signal; Tumor origin
    DOI:  https://doi.org/10.1007/s12015-023-10508-2
  10. Cancers (Basel). 2023 Jan 06. pii: 376. [Epub ahead of print]15(2):
    The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited.
    Kevin Dzobo, Dimakatso A Senthebane, Collet Dandara.
      Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.
    Keywords:  ECM; cancer hallmarks; drug resistance; exosomes; hypoxia; immune cells; stromal cells; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15020376
  11. J Biol Chem. 2023 Jan 12. pii: S0021-9258(23)00036-4. [Epub ahead of print] 102904
    Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.
    Eloisa A Vilas-Boas, João Victor Cabral-Costa, Vitor M Ramos, Camille C Caldeira da Silva, Alicia J Kowaltowski.
      Calcium (Ca2+) is a key regulator in diverse intracellular signaling pathways, and has long been implicated in metabolic control and mitochondrial function. Mitochondria can actively take up large amounts of Ca2+, thereby acting as important intracellular Ca2+ buffers and affecting cytosolic Ca2+ transients. Excessive mitochondrial matrix Ca2+ is known to be deleterious due to opening of the mitochondrial permeability transition pore (mPTP) and consequent membrane potential dissipation, leading to mitochondrial swelling, rupture, and cell death. Moderate Ca2+ within the organelle, on the other hand, can directly or indirectly activate mitochondrial matrix enzymes, possibly impacting on ATP production. Here, we aimed to determine in a quantitative manner if extra or intramitochondrial Ca2+ modulate oxidative phosphorylation in mouse liver mitochondria and intact hepatocyte cell lines. To do so, we monitored the effects of more modest versus supra-physiological increases in cytosolic and mitochondrial Ca2+ on oxygen consumption rates. Isolated mitochondria present increased respiratory control ratios (a measure of oxidative phosphorylation efficiency) when incubated with low (2.4 ± 0.6 μM) and medium (22.0 ± 2.4 μM) Ca2+ concentrations in the presence of complex I-linked substrates pyruvate plus malate and α-ketoglutarate, respectively, but not complex II-linked succinate. In intact cells, both low and high cytosolic Ca2+ led to decreased respiratory rates, while ideal rates were present under physiological conditions. High Ca2+ decreased mitochondrial respiration in a substrate-dependent manner, mediated by mPTP. Overall, our results uncover a Goldilocks effect of Ca2+ on liver mitochondria, with specific "just right" concentrations that activate oxidative phosphorylation.
    Keywords:  calcium transport; electron transfer chain; metabolic flux; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2023.102904
  12. Cureus. 2023 Jan;15(1): e33729
    The Successful Implementation of a Modified Pediatric Acute Lymphoblastic Leukemia Protocol to Treat an Elderly Patient With T-cell Lymphoblastic Leukemia: A Case Report.
    Ibraheem H Motabi, Yara A Alsaif, Mohammed K Bin Shuayl, Faisal M Farwana, Abdulaziz T Alhassan, Faisal A Alsaif.
      Acute lymphoblastic leukemia (ALL) is a group of hematological malignancies most commonly seen in pediatrics. The disease process localizes in lymphoid organs, the central nervous system, the mediastinum, and bone marrow (BM). The clinical features of T-cell acute lymphoblastic leukemia (T-ALL) in adults include evidence of generalized lymphadenopathy, hepatosplenomegaly, immunosuppression, and hypercalcemia. There is limited research on the efficacy of using modified pediatric treatment regimens in the elderly over the age of 60 with ALL; this case report aims to illustrate the successful treatment of a 67-year-old male patient diagnosed with T-ALL, using a modified Children's Oncology Group (COG) protocol. Through this, it has been shown to be an effective, safe, and efficacious treatment option for our patient.
    Keywords:  acute lymphoblastic leukemia (all); adult t-cell leukemia-lymphoma (atll); children's oncology group; hematological malignancies; t-cell leukemia; treatment of all
    DOI:  https://doi.org/10.7759/cureus.33729
  13. Diagnostics (Basel). 2023 Jan 16. pii: 325. [Epub ahead of print]13(2):
    Prognostic Role of CD200 in Acute Lymphoblastic Leukemia Patients.
    Mohamed Khalil, Nahla Elsharkawy, Mona Mohsen Elmawardy, Mahmoud Aly Ayoub.
       BACKGROUND: Overexpression of CD200 in ALL patients indicates that it may be useful in the characterization of leukemia initiating cells (LIC). We aim at investigating the expression pattern of CD200 on leukemic B cells and the correlation of CD200 expression with various clinical and laboratory findings in 62 newly diagnosed acute lymphoblastic leukemia patients.
    METHODS: All patients were subjected to full history taking, a thorough clinical examination, and laboratory investigations, which included complete blood count (CBC), BM aspiration, immunophenotyping of blast cells, and CD200 expression.
    RESULTS: There is a higher statistically significant mean value of CD200 expression among the cases (66.15 ± 23.08) than the control group (0.37 ± 0.2) (p value ≤ 0.001). CD200 expression shows a significant correlation with total leucocytic count and hemoglobin level (p = 0.001, 0.03, respectively).
    CONCLUSIONS: This study showed that CD200 expression was expressed in 100% of the patients. Correlations between CD200 expression and different laboratory data of patients revealed that there was an impact of CD200 on different diagnostic findings. After the follow-up of the patients, we found that the use of PRISM function of the software could add value to the detection of minimal residual disease.
    Keywords:  CD200; acute lymphocytic leukemia; minimal residual disease
    DOI:  https://doi.org/10.3390/diagnostics13020325
  14. Cancer Res. 2023 Jan 18. 83(2): 170-172
    Are There Specific Cancer Stem Cell Markers?
    Linxiang Lan, Axel Behrens.
      The cancer stem cell (CSC) model states that heterogeneous tumor cell populations are organized in a hierarchical manner, with a small population of CSCs at the apex. These CSCs are capable of self-renewal and giving rise to other cancer cell populations, conceptually analogous to the function of normal adult stem cells present in almost all organs. However, there has been significant controversy regarding the existence and identification of CSCs. We argue that technical differences in experimentation and CSC assays, CSC niche-dependency and plasticity, and CSC heterogeneity itself may explain some of the differences observed.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2053
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