bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–10–30
fiveteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Targeted Anti-Mitochondrial Therapy: The Future of Oncology.
  2. Systematic molecular profiling of acute leukemia cancer stem cells allows identification of druggable targets.
  3. UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.
  4. Redox-Regulation in Cancer Stem Cells.
  5. Searching for the Metabolic Signature of Cancer: A Review from Warburg's Time to Now.
  6. Treatment options for acute myeloid leukemia patients aged <60 years.
  7. Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation.
  8. OPA1 drives macrophage metabolism and functional commitment via p65 signaling.
  9. Regulation of Lipid Metabolism Under Stress and Its Role in Cancer.
  10. Approaches towards Elucidating the Metabolic Program of Hematopoietic Stem/Progenitor Cells.
  11. Understanding the Crosstalk Between Epigenetics and Immunometabolism to Combat Cancer.
  12. The immunometabolic landscape of the bone marrow microenvironment in acute myeloid leukemia.
  13. Targeting amino acid metabolism in cancer.
  14. Combination strategies to target metabolic flexibility in cancer.
  15. Cancer stem cells in immunoregulation and bypassing anti-checkpoint therapy.
  1. Genes (Basel). 2022 Sep 26. pii: 1728. [Epub ahead of print]13(10):
    Targeted Anti-Mitochondrial Therapy: The Future of Oncology.
    Farzad Taghizadeh-Hesary, Hassan Akbari, Moslem Bahadori, Babak Behnam.
      Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells' survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.
    Keywords:  ATP; T cell; cancer cell; cancer stem cell; cancer treatment; mitochondria
    DOI:  https://doi.org/10.3390/genes13101728
  2. Heliyon. 2022 Oct;8(10): e11093
    Systematic molecular profiling of acute leukemia cancer stem cells allows identification of druggable targets.
    Abbas Salavaty, Sara Alaei Shehni, Mirana Ramialison, Peter D Currie.
      Acute myeloid leukemia (AML) is one of the most prevalent and acute blood cancers with a poor prognosis and low overall survival rate, especially in the elderly. Although several new AML markers and drug targets have been recently identified, the rate of long-term cancer eradication has not improved significantly due to the presence and drug resistance of AML cancer stem cells (CSCs). Here we develop a novel computational pipeline to analyze the transcriptomic profiles of AML cancer (stem) cells and identify novel candidate AML CSC markers and drug targets. In our novel pipeline we apply a top-down meta-analysis strategy to integrate The Cancer Genome Atlas data with CSC datasets to infer cell stemness features. As a result, a set of genes termed the "AML key CSC genes" along with all the available drugs/compounds that could target them were identified. Overall, our novel computational pipeline could retrieve known cancer drugs (Carfilzomib) and predicted novel drugs such as Zonisamide, Amitriptyline, and their targets amongst the top ranked drugs and drug targets for targeting AML. Additionally, the pipeline applied in this study could be used for the identification of CSC-specific markers, drivers and their respective targeting drugs in other cancer types.
    Keywords:  AML; Amitriptyline; CA1; Cancer stem cells; Carfilzomib; Drug repurposing; MAOB; TNFSF4; Zonisamide
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e11093
  3. Front Immunol. 2022 ;13 960226
    UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.
    Tiphaine Sancerni, Ophélie Renoult, Angèle Luby, Cédric Caradeuc, Véronique Lenoir, Mikael Croyal, Céline Ransy, Esther Aguilar, Catherine Postic, Gildas Bertho, Renaud Dentin, Carina Prip-Buus, Claire Pecqueur, Marie-Clotilde Alves-Guerra.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T cell progenitors. Since relapsed T-ALL is associated with a poor prognosis improving initial treatment of patients is essential to avoid resistant selection of T-ALL. During initiation, development, metastasis and even in response to chemotherapy, tumor cells face strong metabolic challenges. In this study, we identify mitochondrial UnCoupling Protein 2 (UCP2) as a tricarboxylic acid (TCA) cycle metabolite transporter controlling glutamine metabolism associated with T-ALL cell proliferation. In T-ALL cell lines, we show that UCP2 expression is controlled by glutamine metabolism and is essential for their proliferation. Our data show that T-ALL cell lines differ in their substrate dependency and their energetic metabolism (glycolysis and oxidative). Thus, while UCP2 silencing decreases cell proliferation in all leukemia cells, it also alters mitochondrial respiration of T-ALL cells relying on glutamine-dependent oxidative metabolism by rewiring their cellular metabolism to glycolysis. In this context, the function of UCP2 in the metabolite export of malate enables appropriate TCA cycle to provide building blocks such as lipids for cell growth and mitochondrial respiration. Therefore, interfering with UCP2 function can be considered as an interesting strategy to decrease metabolic efficiency and proliferation rate of leukemia cells.
    Keywords:  UCP2; glutamine; leukemia; metabolism rewiring; metabolite carrier; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2022.960226
  4. Biomedicines. 2022 Sep 27. pii: 2413. [Epub ahead of print]10(10):
    Redox-Regulation in Cancer Stem Cells.
    Uwe Lendeckel, Carmen Wolke.
      Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.
    Keywords:  CD13; Nrf2-sinaling; ROS; Sonic Hedgehog signaling; Wnt-signaling; antioxidant signaling pathways; cancer stem cell; drug resistance
    DOI:  https://doi.org/10.3390/biomedicines10102413
  5. Biomolecules. 2022 Oct 02. pii: 1412. [Epub ahead of print]12(10):
    Searching for the Metabolic Signature of Cancer: A Review from Warburg's Time to Now.
    Pierre Jacquet, Angélique Stéphanou.
      This review focuses on the evolving understanding that we have of tumor cell metabolism, particularly glycolytic and oxidative metabolism, and traces back its evolution through time. This understanding has developed since the pioneering work of Otto Warburg, but the understanding of tumor cell metabolism continues to be hampered by misinterpretation of his work. This has contributed to the use of the new concepts of metabolic switch and metabolic reprogramming， that are out of step with reality. The Warburg effect is often considered to be a hallmark of cancer, but is it really? More generally, is there a metabolic signature of cancer? We draw the conclusion that the signature of cancer cannot be reduced to a single factor, but is expressed at the tissue level in terms of the capacity of cells to dynamically explore a vast metabolic landscape in the context of significant environmental heterogeneities.
    Keywords:  Warburg effect; metabolic landscape; metabolic reprogramming; metabolic switch; reverse Warburg
    DOI:  https://doi.org/10.3390/biom12101412
  6. Front Oncol. 2022 ;12 897220
    Treatment options for acute myeloid leukemia patients aged <60 years.
    Giuseppe Visani, Martina Chiarucci, Sara Paolasini, Federica Loscocco, Alessandro Isidori.
      Treatment of acute myeloid leukemia (AML) has changed over the last few years, after the discovery of new drugs selectively targeting AML blasts. Although 3/7 remains the standard of care for most AML patients, several new targeted agents (such as FLT3 inhibitors, CPX-351, gemtuzumab ozogamicin, BCL-2 inhibitor, and oral azacitidine), either as single agents or combined with standard chemotherapy, are approaching clinical practice, starting a new era in AML management. Moreover, emerging evidence has demonstrated that high-risk AML patients might benefit from both allogeneic stem cell transplant and maintenance therapy, providing new opportunities, as well as new challenges, for treating clinicians. In this review, we summarize available data on first-line therapy in young AML patients focusing on targeted therapies, integrating established practice with new evidence, in the effort to outline the contours of a new therapeutic paradigm, that of a "total therapy", which goes beyond obtaining complete remission.
    Keywords:  AML - acute myeloid leukemia; allogeneic stem cell transplantation; induction; target therapy; young
    DOI:  https://doi.org/10.3389/fonc.2022.897220
  7. J Hematol Oncol. 2022 Oct 26. 15(1): 156
    Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation.
    Wonhyoung Seo, Seungyeul Yoo, Yi Zhong, Sang-Hee Lee, Soo-Yeon Woo, Hee-Seon Choi, Minho Won, Taylor Roh, Sang Min Jeon, Kyeong Tae Kim, Prashanta Silwal, Min Joung Lee, Jun Young Heo, Nathan Lawlor, Sup Kim, Dongjun Lee, Jin-Man Kim, Ik-Chan Song, Jun Zhu, Eun-Kyeong Jo.
      Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood. In this study, we investigated the oncogenic functions of ERRα in AML by combining in silico, in vitro, and in vivo analyses and showed ERRα is a key regulator of mtOXPHOS in AML cells. The increased ERRα level was associated with worse clinical outcomes of AML patients. Single cell RNA-Seq analysis of human primary AML cells indicated that ERRα-expressing cancer cells had significantly higher mtOXPHOS enrichment scores. Blockade of ERRα by pharmacologic inhibitor (XCT-790) or gene silencing suppressed mtOXPHOS and increased anti-leukemic effects in vitro and in xenograft mouse models.
    Keywords:  AML; Apoptosis; ERRα; Mitochondrial oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s13045-022-01372-7
  8. Cell Death Differ. 2022 Oct 28.
    OPA1 drives macrophage metabolism and functional commitment via p65 signaling.
    Ricardo Sánchez-Rodríguez, Caterina Tezze, Andrielly H R Agnellini, Roberta Angioni, Francisca C Venegas, Chiara Cioccarelli, Fabio Munari, Nicole Bertoldi, Marcella Canton, Maria Andrea Desbats, Leonardo Salviati, Rosanna Gissi, Alessandra Castegna, Maria Eugenia Soriano, Marco Sandri, Luca Scorrano, Antonella Viola, Barbara Molon.
      Macrophages are essential players for the host response against pathogens, regulation of inflammation and tissue regeneration. The wide range of macrophage functions rely on their heterogeneity and plasticity that enable a dynamic adaptation of their responses according to the surrounding environmental cues. Recent studies suggest that metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the metabolic pathways orchestrating macrophage activation are still under scrutiny. Optic atrophy 1 (OPA1) is a mitochondria-shaping protein controlling mitochondrial fusion, cristae biogenesis and respiration; clear evidence shows that the lack or dysfunctional activity of this protein triggers the accumulation of metabolic intermediates of the TCA cycle. In this study, we show that OPA1 has a crucial role in macrophage activation. Selective Opa1 deletion in myeloid cells impairs M1-macrophage commitment. Mechanistically, Opa1 deletion leads to TCA cycle metabolite accumulation and defective NF-κB signaling activation. In an in vivo model of muscle regeneration upon injury, Opa1 knockout macrophages persist within the damaged tissue, leading to excess collagen deposition and impairment in muscle regeneration. Collectively, our data indicate that OPA1 is a key metabolic driver of macrophage functions.
    DOI:  https://doi.org/10.1038/s41418-022-01076-y
  9. Subcell Biochem. 2022 ;100 81-113
    Regulation of Lipid Metabolism Under Stress and Its Role in Cancer.
    Rimsha Munir, Nousheen Zaidi.
      Within the tumor microenvironment, cancer cells are often exposed to oxygen and nutrient deficiency, leading to various changes in their lipid composition and metabolism. These alterations have important therapeutic implications as they affect the cancer cells' survival, membrane dynamics, and therapy response. This chapter provides an overview of recent insights into the regulation of lipid metabolism in cancer cells under metabolic stress. We discuss how this metabolic adaptation helps cancer cells thrive in a harsh tumor microenvironment.
    Keywords:  Cancer; De Novo Fatty acid synthesis; Fatty acid synthase; Hypoxia; Lipid metabolism; Lipidomic profiles; Metabolic stress; Nutrient deprivation
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_3
  10. Cells. 2022 Oct 11. pii: 3189. [Epub ahead of print]11(20):
    Approaches towards Elucidating the Metabolic Program of Hematopoietic Stem/Progenitor Cells.
    Hiroshi Kobayashi, Shintaro Watanuki, Keiyo Takubo.
      Hematopoietic stem cells (HSCs) in bone marrow continuously supply a large number of blood cells throughout life in collaboration with hematopoietic progenitor cells (HPCs). HSCs and HPCs are thought to regulate and utilize intracellular metabolic programs to obtain metabolites, such as adenosine triphosphate (ATP), which is necessary for various cellular functions. Metabolites not only provide stem/progenitor cells with nutrients for ATP and building block generation but are also utilized for protein modification and epigenetic regulation to maintain cellular characteristics. In recent years, the metabolic programs of tissue stem/progenitor cells and their underlying molecular mechanisms have been elucidated using a variety of metabolic analysis methods. In this review, we first present the advantages and disadvantages of the current approaches applicable to the metabolic analysis of tissue stem/progenitor cells, including HSCs and HPCs. In the second half, we discuss the characteristics and regulatory mechanisms of HSC metabolism, including the decoupling of ATP production by glycolysis and mitochondria. These technologies and findings have the potential to advance stem cell biology and engineering from a metabolic perspective and to establish therapeutic approaches.
    Keywords:  bone marrow environment; hematopoietic progenitor cells; hematopoietic stem cells; metabolome analysis; single cell metabolic analysis; stem cell metabolism; tracer analysis
    DOI:  https://doi.org/10.3390/cells11203189
  11. Subcell Biochem. 2022 ;100 581-616
    Understanding the Crosstalk Between Epigenetics and Immunometabolism to Combat Cancer.
    Anuradha Seth, Susanta Kar.
      The interaction between metabolic and epigenetic events shapes metabolic adaptations of cancer cells and also helps rewire the proliferation and activity of surrounding immune cells in the tumor microenvironment (TME). Recent studies indicate that the TME imposes metabolic constraints on immune cells, inducing them to attain a tolerogenic state, incompetent of mounting effective tumor eradication. Owing to extensive mutations acquired over repeated cell divisions, tumor cells selectively accumulate metabolites that regulate the activity of key epigenetic enzymes to mediate activation/suppression of genes associated with T-cell function and macrophage polarization. Further, multiple modulators connecting epigenetic and metabolic pathways help dictate the preferential induction of cytokines and expression of lineage-specifying genes associated with immunosuppressive T-cell differentiation.In this chapter, we attempt to discuss the mechanisms underpinning the metabolic and epigenetic interplay in immune cells of the TME and how modulating these events can boost the application of existing anticancer immunotherapy.
    Keywords:  Cancer immune cell; DNA methylation; Epigenetics; Histone acetylation; Histone methylation; Oncometabolites
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_18
  12. Exp Hematol Oncol. 2022 Oct 28. 11(1): 81
    The immunometabolic landscape of the bone marrow microenvironment in acute myeloid leukemia.
    Binyan Xu, Ziying Zhou, Yueting Wen, Zhongwei Li, Zhongxi Huang, Yuhua Li.
      The bone marrow microenvironment of acute myeloid leukemia (AML) consists of various cell types and signaling factors, which serve as a niche supporting leukemia cells in their invasion of the human body. However, a systematic landscape of metabolic heterogeneity and its relationship with immunity in the AML microenvironment at single-cell resolution has not yet been established. Herein, we addressed this issue by analyzing 208,543 bone marrow cells from 40 AML patients and 3 healthy donors obtained from GSE130756. We focused on the metabolic preference of AML progenitor cells and diverse immune cells, especially myeloid immune cells and T cells. Accordingly, the immune evasion mechanism of leukemia cells was proposed from the view of the allocation of energy and oxygen, providing a novel direction of treatment. Finally, we tentatively proposed potential targets for AML metabolic therapy, including ENO1, GSTP1, MT-ND4L and UQCR11. Collectively, our analysis facilitates the development of personalized therapies targeting unique immunometabolic profiles.
    DOI:  https://doi.org/10.1186/s40164-022-00332-8
  13. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00109-5. [Epub ahead of print]373 37-79
    Targeting amino acid metabolism in cancer.
    Lucie Safrhansova, Katerina Hlozkova, Julia Starkova.
      Metabolic rewiring is a characteristic hallmark of cancer cells. This phenomenon sustains uncontrolled proliferation and resistance to apoptosis by increasing nutrients and energy supply. However, reprogramming comes together with vulnerabilities that can be used against tumor and can be applied in targeted therapy. In the last years, the genetic background of tumors has been identified thoroughly and new therapies targeting those mutations tested. Nevertheless, we propose that targeting the phenotype of cancer cells could be another way of treatment aiming to avoid drug resistance and non-responsiveness of cancer patients. Amino acid metabolism is part of the altered processes in cancer cells. Amino acids are building blocks and also sensors of signaling pathways regulating main biological processes. In this comprehensive review, we described four amino acids (asparagine, arginine, methionine, and cysteine) which have been actively investigated as potential targets for anti-tumor therapy. Asparagine depletion is successfully used for decades in the treatment of acute lymphoblastic leukemia and there is a strong implication to apply it to other types of tumors. Arginine auxotrophic tumors are great candidates for arginine-starvation therapy. Higher requirement for essential amino acids such as methionine and cysteine point out promising targetable weaknesses of cancer cells.
    Keywords:  Amino acid metabolism; Arginine; Asparagine; Cancer; Cysteine; Methionine; Targeted therapy
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.08.001
  14. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00022-3. [Epub ahead of print]373 159-197
    Combination strategies to target metabolic flexibility in cancer.
    Jelena Krstic, Katharina Schindlmaier, Andreas Prokesch.
      Therapeutically interfering with metabolic pathways has great merit to curtail tumor growth because the demand for copious amounts of energy for growth-supporting biomass production is common to all cancer entities. A major impediment to a straight implementation of metabolic cancer therapy is the metabolic flexibility and plasticity of cancer cells (and their microenvironment) resulting in therapy resistance and evasion. Metabolic combination therapies, therefore, are promising as they are designed to target several energetic routes simultaneously and thereby diminish the availability of alternative substrates. Thus, dietary restrictions, specific nutrient limitations, and/or pharmacological interventions impinging on metabolic pathways can be combined to improve cancer treatment efficacy, to overcome therapy resistance, or even act as a preventive measure. Here, we review the most recent developments in metabolic combination therapies particularly highlighting in vivo reports of synergistic effects and available clinical data. We close with identifying the challenges of the field (metabolic tumor heterogeneity, immune cell interactions, inter-patient variabilities) and suggest a "metabo-typing" strategy to tailor evidence-based metabolic combination therapies to the energetic requirements of the tumors and the patient's nutritional habits and status.
    Keywords:  Cancer; Combination therapy; Dietary restriction; Metabolic flexibility
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.03.001
  15. Biomed Pharmacother. 2022 Oct 25. pii: S0753-3322(22)01295-1. [Epub ahead of print]156 113906
    Cancer stem cells in immunoregulation and bypassing anti-checkpoint therapy.
    Elnaz Rouzbahani, Jamal Majidpoor, Sajad Najafi, Keywan Mortezaee.
      Tumor microenvironment (TME) takes critical roles in tumor resistance to immune checkpoint inhibitors (ICIs) including anti-programmed death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1). Cancer stem cells (CSCs) are one of the key components of TME that play important roles in immunoregulation and therapy resistance. CSCs suppress CD8+ T cell infiltration, and promote recruitment of type 2 macrophages (M2) and the activity of type 2 neutrophils (N2). There is a positive association between CSC expansion with high PD-L1 expression in TME, and the expression of PD-L1 is higher in CSCs than cancer cells. PD-L1 expression in metastatic cancer cells induces a dedifferentiation program through stimulating an epithelial-mesenchymal transition (EMT) profile, thereby replenishing CSC proportion inside tumor. Conversion from EMT to mesenchymal-epithelial transition (MET) downregulates PD-L1 expression on CSCs and non-CSCs and increases ICI efficacy. There is an evidence of CSC replenishment secondary to the anti-PD-1 therapy. Targeting CSCs is, in fact, a key step in effective tumor breakdown and reducing tumor recurrence after immunotherapy. A number of signaling are involved in CSC enrichment within tumor area, among them a key focus is over transforming growth factor-β (TGF-β). TGF-β induces a dedifferentiation program, and its activity as a bridge between EMT with increased PD-L1 level rationalizes application of dual TGF-β/anti-PD-L1 inhibitors as an effective strategy for reinvigorating immunoactivities in patients under ICI therapy. In this review, we aimed to discuss about connections between CSCs with immune ecosystem of tumor and the impact of such interactions on cancer responses to ICI therapy.
    Keywords:  Cancer stem cell (CSC); Heterogeneity; Immune checkpoint inhibitor (ICI); Programmed death-1 (PD-1); Programmed death-ligand 1 (PD-L1); Transforming growth factor-β (TGF-β); Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.biopha.2022.113906
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