bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–04–30
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.
  2. The Warburg effect: a signature of mitochondrial overload.
  3. Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.
  4. Editorial: Cancer and nutrients: new chemicals, signals, and biomarker-based therapy.
  5. Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy.
  6. ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives.
  7. The role of cholesterol metabolism in tumor therapy, from bench to bed.
  8. Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects.
  9. Implication of Dynamin-2 (DNM2) Mutations in Adult T-cell Acute Lymphoblastic Leukemia.
  10. Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis.
  1. Metabolites. 2023 Mar 24. pii: 467. [Epub ahead of print]13(4):
    Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.
    Rachel Culp-Hill, Brett M Stevens, Courtney L Jones, Shanshan Pei, Monika Dzieciatkowska, Mohammad Minhajuddin, Craig T Jordan, Angelo D'Alessandro.
      Recent advances in targeting leukemic stem cells (LSCs) using venetoclax with azacitidine (ven + aza) has significantly improved outcomes for de novo acute myeloid leukemia (AML) patients. However, patients who relapse after traditional chemotherapy are often venetoclax-resistant and exhibit poor clinical outcomes. We previously described that fatty acid metabolism drives oxidative phosphorylation (OXPHOS) and acts as a mechanism of LSC survival in relapsed/refractory AML. Here, we report that chemotherapy-relapsed primary AML displays aberrant fatty acid and lipid metabolism, as well as increased fatty acid desaturation through the activity of fatty acid desaturases 1 and 2, and that fatty acid desaturases function as a mechanism of recycling NAD+ to drive relapsed LSC survival. When combined with ven + aza, the genetic and pharmacologic inhibition of fatty acid desaturation results in decreased primary AML viability in relapsed AML. This study includes the largest lipidomic profile of LSC-enriched primary AML patient cells to date and indicates that inhibition of fatty acid desaturation is a promising therapeutic target for relapsed AML.
    Keywords:  acute myeloid leukemia; fatty acid metabolism; leukemic stem cells; lipidomics
    DOI:  https://doi.org/10.3390/metabo13040467
  2. Trends Cell Biol. 2023 Apr 26. pii: S0962-8924(23)00070-3. [Epub ahead of print]
    The Warburg effect: a signature of mitochondrial overload.
    Yahui Wang, Gary J Patti.
      A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.
    Keywords:  Warburg effect; aerobic fermentation; aerobic glycolysis; cancer metabolism; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.013
  3. Cell Stem Cell. 2023 Apr 19. pii: S1934-5909(23)00119-4. [Epub ahead of print]
    Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.
    Sergi Beneyto-Calabuig, Anne Kathrin Merbach, Jonas-Alexander Kniffka, Magdalena Antes, Chelsea Szu-Tu, Christian Rohde, Alexander Waclawiczek, Patrick Stelmach, Sarah Gräßle, Philip Pervan, Maike Janssen, Jonathan J M Landry, Vladimir Benes, Anna Jauch, Michaela Brough, Marcus Bauer, Birgit Besenbeck, Julia Felden, Sebastian Bäumer, Michael Hundemer, Tim Sauer, Caroline Pabst, Claudia Wickenhauser, Linus Angenendt, Christoph Schliemann, Andreas Trumpp, Simon Haas, Michael Scherer, Simon Raffel, Carsten Müller-Tidow, Lars Velten.
      Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.
    Keywords:  AML; CSC; HSC; LSC; acute myeloid leukemia; cancer stem cells; cellular differentiation; computational biology; computational method; hematopoietic stem cells; leukemic stem cells; single-cell RNA-seq; single-cell genomics; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.stem.2023.04.001
  4. Front Oncol. 2023 ;13 1190065
    Editorial: Cancer and nutrients: new chemicals, signals, and biomarker-based therapy.
    Xian-Yang Qin, Marco Antonio Mendoza-Parra, Yohei Shirakami.
      
    Keywords:  cancer metabolism; cancer prognosis; chemoprevention; nutrition; precision medicine
    DOI:  https://doi.org/10.3389/fonc.2023.1190065
  5. Clin Exp Med. 2023 Apr 24.
    Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy.
    Amit B Tewari, Anamika Saini, Deepika Sharma.
      Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy.
    Keywords:  Cancer stem cells; Chemotherapy; Differentiation agents; Differentiation therapy; Hyperthermia therapy; miRNA
    DOI:  https://doi.org/10.1007/s10238-023-01066-5
  6. Int J Mol Sci. 2023 Apr 12. pii: 7147. [Epub ahead of print]24(8):
    ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives.
    Daniela Damiani, Mario Tiribelli.
      Despite recent advances, prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to poor response to therapy or relapse. Among causes of resistance, over-expression of multidrug resistance (MDR) proteins represents a pivotal mechanism. ABCG2 is an efflux transporter responsible for inducing MDR in leukemic cells; through its ability to extrude many antineoplastic drugs, it leads to AML resistance and/or relapse, even if conflicting data have been reported to date. Moreover, ABCG2 may be co-expressed with other MDR-related proteins and is finely regulated by epigenetic mechanisms. Here, we review the main issues regarding ABCG2 activity and regulation in the AML clinical scenario, focusing on its expression and the role of polymorphisms, as well as on the potential ways to inhibit its function to counteract drug resistance to, eventually, improve outcomes in AML patients.
    Keywords:  ABCG2; acute myeloid leukemia; counteraction; multidrug resistance; prognosis; survival
    DOI:  https://doi.org/10.3390/ijms24087147
  7. Front Pharmacol. 2023 ;14 928821
    The role of cholesterol metabolism in tumor therapy, from bench to bed.
    Wenhao Xia, Hao Wang, Xiaozhu Zhou, Yan Wang, Lixiang Xue, Baoshan Cao, Jiagui Song.
      Cholesterol and its metabolites have important biological functions. Cholesterol is able to maintain the physical properties of cell membrane, play an important role in cellular signaling, and cellular cholesterol levels reflect the dynamic balance between biosynthesis, uptake, efflux and esterification. Cholesterol metabolism participates in bile acid production and steroid hormone biosynthesis. Increasing evidence suggests a strict link between cholesterol homeostasis and tumors. Cholesterol metabolism in tumor cells is reprogrammed to differ significantly from normal cells, and disturbances of cholesterol balance also induce tumorigenesis and progression. Preclinical and clinical studies have shown that controlling cholesterol metabolism suppresses tumor growth, suggesting that targeting cholesterol metabolism may provide new possibilities for tumor therapy. In this review, we summarized the metabolic pathways of cholesterol in normal and tumor cells and reviewed the pre-clinical and clinical progression of novel tumor therapeutic strategy with the drugs targeting different stages of cholesterol metabolism from bench to bedside.
    Keywords:  cholesterol; cholesterol metabolism; clinical trial; pharmacological targets; tumor therapy
    DOI:  https://doi.org/10.3389/fphar.2023.928821
  8. Molecules. 2023 Apr 21. pii: 3624. [Epub ahead of print]28(8):
    Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects.
    Bimala Dhakal, Yoko Tomita, Paul Drew, Timothy Price, Guy Maddern, Eric Smith, Kevin Fenix.
      Cancer metabolic plasticity, including changes in fatty acid metabolism utilisation, is now widely appreciated as a key driver for cancer cell growth, survival and malignancy. Hence, cancer metabolic pathways have been the focus of much recent drug development. Perhexiline is a prophylactic antianginal drug known to act by inhibiting carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), mitochondrial enzymes critical for fatty acid metabolism. In this review, we discuss the growing evidence that perhexiline has potent anti-cancer properties when tested as a monotherapy or in combination with traditional chemotherapeutics. We review the CPT1/2 dependent and independent mechanisms of its anti-cancer activities. Finally, we speculate on the clinical feasibility and utility of repurposing perhexiline as an anti-cancer agent, its limitations including known side effects and its potential added benefit of limiting cardiotoxicity induced by other chemotherapeutics.
    Keywords:  anti-cancer; cancer metabolism; cardiotoxicity; perhexiline; repurposing
    DOI:  https://doi.org/10.3390/molecules28083624
  9. Asian Pac J Cancer Prev. 2023 Apr 01. pii: 90577. [Epub ahead of print]24(4): 1257-1264
    Implication of Dynamin-2 (DNM2) Mutations in Adult T-cell Acute Lymphoblastic Leukemia.
    Marwa Sobh, Salah Aref, Mohamed Al Agdar, Maha El Zafrany, Ahmed M A El-Sokkary.
       BACKGROUND: The objective of the present study was to improve the risk stratification of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients. It aimed to identify the frequency and clinical impact of DNM2 gene mutations among adult T-ALL cases.
    METHODS: The current study included 25 T-ALL patients before starting their treatment. Mutational analysis of DNM2 gene (exons 18 and 22) was performed for all patients using Macrogen 3730 apparatus.
    RESULTS: We identified DNM2 gene mutations in 19 out of 25 (76%) patients. The detected mutations were either missense or deletion. Only active mutations (deletion) were associated with poor induction remission response and high frequency of relapse. Two novel mutations were addressed among the studied cohort of patients. They included c.1866G>C (p.V596L) and c.1872delA in exon 18. A high frequency of silent mutations was also found in T-ALL patients, but with no impact on clinical features.
    CONCLUSION: The DNM2 mutations were prevalent among adult T-ALL patients and might have a role in the pathogenesis of the disease. Active DNM2 mutations were associated with poor clinical outcome. Moreover, high frequency of DNM2 mutations indicated that these mutations could be utilized in detection of minimal residual disease in T-ALL patients.
    Keywords:  DNM 2; Prognosis; adult T-cell acute lymphoblastic leukemia; mutations
    DOI:  https://doi.org/10.31557/APJCP.2023.24.4.1257
  10. Int J Mol Sci. 2023 Apr 11. pii: 7076. [Epub ahead of print]24(8):
    Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis.
    Nan Niu, Jinfeng Ye, Zhangli Hu, Junbin Zhang, Yun Wang.
      One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.
    Keywords:  glycolysis; malignant proliferation; metabolic plasticity; mitochondrial oxidative phosphorylation; tumorigenesis
    DOI:  https://doi.org/10.3390/ijms24087076
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