bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–07–10
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication.
  2. GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia.
  3. The new metabolic needs of hematopoietic stem cells.
  4. The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors.
  5. Metabolic Regulation of Hematopoietic Stem Cells.
  6. DNA damage and metabolic mechanisms of cancer drug resistance.
  7. Theragnostic Strategies Harnessing the Self-Renewal Pathways of Stem-like Cells in the Acute Myeloid Leukemia.
  8. Venetoclax resistance: mechanistic insights and future strategies.
  9. Regulation of mitochondrial temperature in health and disease.
  10. Cancer metabolism control by natural products: Pyruvate kinase M2 targeting therapeutics.
  1. Cancer Drug Resist. 2022 ;5(2): 344-367
    Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication.
    Quinty Hansen, Costa Bachas, Linda Smit, Jacqueline Cloos.
      In acute myeloid leukemia (AML), a small cell population that contains stem cell features such as lack of differentiation, self-renewal potential, and drug resistance, can be identified. These so-called leukemic stem cells (LSCs) are thought to be responsible for relapse initiation after initial treatment leading to successful eradication of the bulk AML cell population. Since many studies have aimed to characterize and eliminate LSCs to prevent relapse and increase survival rates of patients, LSCs are one of the best characterized cancer stem cells. The specific elimination of LSCs, while sparing the healthy normal hematopoietic stem cells (HSCs), is one of the major challenges in the treatment of leukemia. This review focuses on several surface markers and intracellular transcription factors that can distinguish AML LSCs from HSCs and, therefore, specifically eliminate these stem cell-like leukemic cells. Moreover, previous and ongoing clinical trials of acute leukemia patients treated with therapies targeting these markers are discussed. In contrast to knowledge on LSCs in AML, insight into LSCs in acute lymphoid leukemia (ALL) is limited. This review therefore also addresses the latest insight into LSCs in ALL.
    Keywords:  Acute myeloid leukemia; acute lymphoid leukemia; leukemic stem cells; targeted therapy
    DOI:  https://doi.org/10.20517/cdr.2021.140
  2. Leukemia. 2022 Jul 08.
    GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia.
    Longlong Liu, Pradeep Kumar Patnana, Xiaoqing Xie, Daria Frank, Subbaiah Chary Nimmagadda, Minhua Su, Donghua Zhang, Thorsten Koenig, Frank Rosenbauer, Marie Liebmann, Luisa Klotz, Wendan Xu, Jan Vorwerk, Felix Neumann, Jana Hüve, Andreas Unger, Jürgen Günther Okun, Bertram Opalka, Cyrus Khandanpour.
      Recent studies highlighted the role of transcription factors in metabolic regulation during hematopoiesis and leukemia development. GFI1B is a transcriptional repressor that plays a critical role in hematopoiesis, and its expression is negatively related to the prognosis of acute myeloid leukemia (AML) patients. We earlier reported a change in the metabolic state of hematopoietic stem cells upon Gfi1b deletion. Here we explored the role of Gfi1b in metabolism reprogramming during hematopoiesis and leukemogenesis. We demonstrated that Gfi1b deletion remarkably activated mitochondrial respiration and altered energy metabolism dependence toward oxidative phosphorylation (OXPHOS). Mitochondrial substrate dependency was shifted from glucose to fatty acids upon Gfi1b deletion via upregulating fatty acid oxidation (FAO). On a molecular level, Gfi1b epigenetically regulated multiple FAO-related genes. Moreover, we observed that metabolic phenotypes evolved as cells progressed from preleukemia to leukemia, and the correlation between Gfi1b expression level and metabolic phenotype was affected by genetic variations in AML cells. FAO or OXPHOS inhibition significantly impeded leukemia progression of Gfi1b-KO MLL/AF9 cells. Finally, we showed that Gfi1b-deficient AML cells were more sensitive to metformin as well as drugs implicated in OXPHOS and FAO inhibition, opening new potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41375-022-01635-9
  3. Curr Opin Hematol. 2022 Jul 01. 29(4): 188-193
    The new metabolic needs of hematopoietic stem cells.
    James Bartram, Marie-Dominique Filippi.
       PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) are endowed with high regenerative potential to supply mature blood cells throughout life, under steady state or stress conditions. HSCs are thought to rely on glycolysis when in a quiescent state and to switch to oxidative phosphorylation to meet their metabolic needs during activation. Recently, a series of important studies reveals a higher degree of complexity that goes well beyond the dichotomy between glycolysis and oxidative phosphorylation. The purpose of this review is to summarize the recent findings highlighting the multifaceted metabolic requirements of HSC homeostasis.
    RECENT FINDINGS: Emerging evidence points to the importance of lysosomal catabolic activity and noncanonical retinoic acid pathway in maintaining HSC quiescence and stemness. HSC activation into cycle seems to be accompanied by a switch to glycolysis-mitochondrial coupling and to anabolic pathways, including Myc, aspartate-mediated purine synthesis.
    SUMMARY: Knowledge of metabolism of HSCs has dramatically increased in the past 2 years and reveals unexpected needs of HSCs during both their quiescent and activated state. Understanding how HSCs use metabolism for their functions will offer new opportunity for HSC-based therapies.
    DOI:  https://doi.org/10.1097/MOH.0000000000000719
  4. Nat Commun. 2022 Jul 04. 13(1): 3833
    The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors.
    Lina Liu, Ana Vujovic, Nandan P Deshpande, Shashank Sathe, Govardhan Anande, He Tian Tony Chen, Joshua Xu, Mark D Minden, Gene W Yeo, Ashwin Unnikrishnan, Kristin J Hope, Yu Lu.
      Chemo-resistance in acute myeloid leukemia (AML) patients is driven by leukemic stem cells (LSCs) resulting in high rates of relapse and low overall survival. Here, we demonstrate that upregulation of the splicing factor, RBM17 preferentially marks and sustains LSCs and directly correlates with shorten patient survival. RBM17 knockdown in primary AML cells leads to myeloid differentiation and impaired colony formation and in vivo engraftment. Integrative multi-omics analyses show that RBM17 repression leads to inclusion of poison exons and production of nonsense-mediated decay (NMD)-sensitive transcripts for pro-leukemic factors and the translation initiation factor, EIF4A2. We show that EIF4A2 is enriched in LSCs and its inhibition impairs primary AML progenitor activity. Proteomic analysis of EIF4A2-depleted AML cells shows recapitulation of the RBM17 knockdown biological effects, including pronounced suppression of proteins involved in ribosome biogenesis. Overall, these results provide a rationale to target RBM17 and/or its downstream NMD-sensitive splicing substrates for AML treatment.
    DOI:  https://doi.org/10.1038/s41467-022-31155-0
  5. Hemasphere. 2022 Jul;6(7): e740
    Metabolic Regulation of Hematopoietic Stem Cells.
    Claudia Morganti, Nina Cabezas-Wallscheid, Keisuke Ito.
      Cellular metabolism is a key regulator of hematopoietic stem cell (HSC) maintenance. HSCs rely on anaerobic glycolysis for energy production to minimize the production of reactive oxygen species and shift toward mitochondrial oxidative phosphorylation upon differentiation. However, increasing evidence has shown that HSCs still maintain a certain level of mitochondrial activity in quiescence, and exhibit high mitochondrial membrane potential, which both support proper HSC function. Since glycolysis and the tricarboxylic acid (TCA) cycle are not directly connected in HSCs, other nutrient pathways, such as amino acid and fatty acid metabolism, generate acetyl-CoA and provide it to the TCA cycle. In this review, we discuss recent insights into the regulatory roles of cellular metabolism in HSCs. Understanding the metabolic requirements of healthy HSCs is of critical importance to the development of new therapies for hematological disorders.
    DOI:  https://doi.org/10.1097/HS9.0000000000000740
  6. Cancer Drug Resist. 2022 ;5(2): 368-379
    DNA damage and metabolic mechanisms of cancer drug resistance.
    Deanna Tiek, Shi-Yuan Cheng.
      Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses. While many pivotal advances have been made in first combination therapies, then targeted therapies, and now broadening out to immunomodulatory drugs or metabolic targeting compounds, drug resistance is still ultimately universally fatal. In this brief review, we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation, focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding microenvironment. In this way, with a better understanding of both targetable mutations in combination with the metabolism, smarter drugs may be designed to combat cancer drug resistance.
    Keywords:  Cancer drug resistance; DNA damage; DNA repair; drug resistance; hypoxia; metabolism; overcoming resistance; synthetic lethality
    DOI:  https://doi.org/10.20517/cdr.2021.148
  7. Crit Rev Oncol Hematol. 2022 Jul 05. pii: S1040-8428(22)00177-9. [Epub ahead of print] 103753
    Theragnostic Strategies Harnessing the Self-Renewal Pathways of Stem-like Cells in the Acute Myeloid Leukemia.
    Rahul Bhattacharjee, Sharad Ghosh, Arijit Nath, Asmita Basu, Ojaswi Biswas, Chandragauda R Patil, Chanakya Nath Kundu.
      Acute myelogenous leukemia (AML) is a genetically heterogeneous and aggressive cancer of the Hematopoietic Stem/progenitor cells. It is distinguished by the uncontrollable clonal growth of malignant myeloid stem cells in the bone marrow, venous blood, and other body tissues. AML is the most predominant of leukemias occurring in adults (25%) and children (15-20%). The relapse after chemotherapy is a major concern in the treatment of AML. The overall 5-year survival rate in young AML patients is about 40-45% whereas in the elderly patients it is less than 10%. Leukemia stem-like cells (LSCs) having the ability to self-renew indefinitely, repopulate and persist longer in the G0/G1 phase play a crucial role in the AML relapse and refractoriness to chemotherapy. Hence, novel treatment strategies and diagnostic biomarkers targeting LSCs are being increasingly investigated. Through this review, we have explored the signaling modulations in the LSCs as the theragnostic targets. The significance of the self-renewal pathways in overcoming the treatment challenges in AML has been highlighted.
    Keywords:  Acute myeloid leukemia; Leukemia stem cells-like cells; chemoresistance; self-renewal pathways; signaling pathways
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103753
  8. Cancer Drug Resist. 2022 ;5(2): 380-400
    Venetoclax resistance: mechanistic insights and future strategies.
    Faustine Ong, Kunhwa Kim, Marina Y Konopleva.
      Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies. Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations. Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.
    Keywords:  Azacitidine; BCL2 protein; Decitabine; Venetoclax; acute myeloid leukemia; human; hypomethylating agents; resistance
    DOI:  https://doi.org/10.20517/cdr.2021.125
  9. Pflugers Arch. 2022 Jul 02.
    Regulation of mitochondrial temperature in health and disease.
    Zaynab El-Gammal, Mohamed A Nasr, Ahmed O Elmehrath, Radwa A Salah, Shams M Saad, Nagwa El-Badri.
      Mitochondrial temperature is produced by various metabolic processes inside the mitochondria, particularly oxidative phosphorylation. It was recently reported that mitochondria could normally operate at high temperatures that can reach 50℃. The aim of this review is to identify mitochondrial temperature differences between normal cells and cancer cells. Herein, we discussed the different types of mitochondrial thermosensors and their advantages and disadvantages. We reviewed the studies assessing the mitochondrial temperature in cancer cells and normal cells. We shed the light on the factors involved in maintaining the mitochondrial temperature of normal cells compared to cancer cells.
    Keywords:  Heat shock proteins; Mitochondria; Mitochondrial temperature; Oxidative phosphorylation; Uncoupling proteins
    DOI:  https://doi.org/10.1007/s00424-022-02719-2
  10. Phytother Res. 2022 Jul 06.
    Cancer metabolism control by natural products: Pyruvate kinase M2 targeting therapeutics.
    Ali H El-Far, Soad K Al Jaouni, Xiaotao Li, Junjiang Fu.
      Glycolysis is the primary source of energy for cancer growth and metastasis. The shift in metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis is called the Warburg effect. Cancer progression due to aerobic glycolysis is often associated with the activation of oncogenes or the loss of tumor suppressors. Therefore, inhibition of glycolysis is one of the effective strategies in cancer control. Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme overexpressed in breast, prostate, lung, colorectal, and liver cancers. Here, we discuss published studies regarding PKM2 inhibitors from natural products that are promising drug candidates for cancer therapy. We have highlighted the potential of natural PKM2 inhibitors for various cancer types. Moreover, we encourage researchers to evaluate the combinational effects between natural and synthetic PKM2 inhibitors. Also, further high-quality studies are needed to firmly establish the clinical efficacy of natural products.
    Keywords:  PKM2 inhibitors; glycolysis; natural products; pyruvate kinase M2 (PKM2)
    DOI:  https://doi.org/10.1002/ptr.7534
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