bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022‒12‒11
eleven papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Contribution of metabolic abnormalities to acute myeloid leukemia pathogenesis.
  2. Triple combination targeting methyltransferase, BCL-2, and PD-1 facilitates antileukemia responses in acute myeloid leukemia.
  3. C1QBP regulates mitochondrial plasticity to impact tumor progression and antitumor immune response.
  4. [Current Status and New Drugs Progress in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia--Review].
  5. Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.
  6. Targeting glycolysis for cancer therapy using drug delivery systems.
  7. The path to venetoclax resistance is paved with mutations, metabolism, and more.
  8. Cancer Stem Cells: Biology and Therapeutic Implications.
  9. GSK3 inhibitor suppresses cell growth and metabolic process in FLT3-ITD leukemia cells.
  10. [Research Progress of Cytokines in the Prognosis of Acute Myeloid Leukemia --Review].
  11. Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression.
  1. Trends Cell Biol. 2022 Dec 05. pii: S0962-8924(22)00255-0. [Epub ahead of print]
    Contribution of metabolic abnormalities to acute myeloid leukemia pathogenesis.
    Grace Egan, Aaron D Schimmer.
      Acute myeloid leukemia (AML) is a malignant disease of myeloid precursors. Somatic mutations have long been accepted as drivers of this malignancy. Over the past decade, unique mitochondrial and metabolic dependencies of AML and AML stem cells have been identified, including a reliance on oxidative phosphorylation. More recently, metabolic enzymes have demonstrated noncanonical roles in regulating gene expression in AML, controlling cell differentiation and stemness. These mitochondrial and metabolic adaptations occur independent of underlying genomic abnormalities and contribute to chemoresistance and relapse. In this opinion article, we discuss the current understanding of AML pathogenesis and whether mitochondrial and metabolic abnormalities drive leukemogenesis or are a non-contributory phenotype.
    Keywords:  acute myeloid leukemia; metabolism; mitochondria; oxidative phosphorylation; pathogenesis
    DOI:  https://doi.org/10.1016/j.tcb.2022.11.004
  2. Cancer. 2022 Dec 07.
    Triple combination targeting methyltransferase, BCL-2, and PD-1 facilitates antileukemia responses in acute myeloid leukemia.
    Zhihong Zeng, Abhishek Maiti, Shelley Herbrich, Tianyu Cai, Antonio Cavazos, Taylor Manzella, Helen Ma, Kala Hayes, Jairo Matthews, Courtney D DiNardo, Naval G Daver, Marina Y Konopleva.
      BACKGROUND: A recent breakthrough therapy combining the BCL-2 inhibitor venetoclax with hypomethylating agents (HMAs) targeting DNA methyltransferase has improved outcomes for patients with acute myeloid leukemia (AML), but the responses and long-term survival in older/unfit patients and in patients with relapsed/refractory AML remain suboptimal. Recent studies showed that inhibition of BCL-2 or DNA methyltransferase modulates AML T-cell immunity.METHODS: By using flow cytometry and time-of-flight mass cytometry, the authors examined the effects of the HMA decitabine combined with the BCL-2 inhibitor venetoclax (DAC/VEN therapy) on leukemia cells and T cells in patients with AML who received DAC/VEN therapy in a clinical trial. The authors investigated the response of programmed cell death protein 1 (PD-1) inhibition in the DAC/VEN-treated samples in vitro and investigated the triple combination of PD-1 inhibition with HMA/venetoclax in the trial patients who had AML.
    RESULTS: DAC/VEN therapy effectively targeted leukemia cells and upregulated the expression of the immune checkpoint-inhibitory receptor PD-1 in T cells while preserving CD4-positive and CD8-positive memory T cells in a subset of patients with AML who were tested. In vitro PD-1 inhibition potentiated the antileukemia response in DAC/VEN-treated AML samples. The combined use of azacitidine, venetoclax, and nivolumab eliminated circulating blasts and leukemia stem cells/progenitor cells and expanded the percentage of CD8-positive memory T cells in an illustrative patient with relapsed AML who responded to the regimen in an ongoing clinical trial.
    CONCLUSIONS: Immunomodulation by targeting PD-1 enhances the therapeutic effect of combining an HMA and venetoclax in patients with AML.
    Keywords:  BCL-2; T-cell immunity; acute myeloid leukemia therapy; co-targeting methyltransferase; immunomodulation; programmed cell death protein 1 (PD-1); programmed cell death protein 1 inhibition
    DOI:  https://doi.org/10.1002/cncr.34566
  3. Front Physiol. 2022 ;13 1012112
    C1QBP regulates mitochondrial plasticity to impact tumor progression and antitumor immune response.
    Qiping Wang, Dafei Chai, Navid Sobhani, Nan Sun, Praveen Neeli, Junnian Zheng, Hui Tian.
      Mitochondrial plasticity including mitochondrial dynamics, metabolic flexibility, and mitochondrial quality control, impact tumor cells' progression and determine immune cells' fate. Complement C1q binding protein (C1QBP) plays an indispensable role through regulating mitochondrial morphology, metabolism, and autophagy. C1QBP promotes mitochondrial plasticity to impact tumor metastasis and their therapeutic response. At the same time, C1QBP is involved in regulating immune cells' maturation, differentiation, and effector function through the enhancement of mitochondrial function. In this regard, manipulation of C1QBP has been shown to adjust the competitive balance between tumor cells and immune cells. In the course of evolution, mitochondrial plasticity has endowed numerous advantages against the relentless microenvironment of tumors. In this current review, we summarize the current knowledge of the mechanism of C1QBP regulation of cancer and immunity. We explain this process in vision of potentially new anticancer therapies.
    Keywords:  C1QBP; antitumor immune response; immunotherapy; metabolic flexibility; mitochondrial plasticity; tumor progression
    DOI:  https://doi.org/10.3389/fphys.2022.1012112
  4. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2022 Dec;30(6): 1907-1911
    [Current Status and New Drugs Progress in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia--Review].
    Wen-Feng Li, Jing-Bo Zhou, Yan-Hong Zhao, Hong-Juan Yu.
      The overall therapeutic outcome of acute myeloid leukemia (AML) is poor, and relapse and refractory are the main reasons for treatment failure. Leukemia cells of relapsed and refractory AML (R/R-AML) patients are usually resistant to conventional chemotherapy, and new treatment regimens are urgently needed to further improve the survival rate and prolong the survival time of these patients.There are no recommended unified treatment regimens other than entering clinical trials.At present,the main options are salvage chemotherapy and hematopoietic stem cell transplantation (HSCT), and HSCT is the only possible cure for R/R-AML, but the prognosis of most of these patients is still poor.In recent years,the treatment status of AML has progressed rapidly, and the new therapies are emerging, many new drugs have become the research focus. Some progress has been made in improving chemosensitivity and overcoming chemoresistance by combining the new drugs with the original chemotherapeutic drugs, which provide a new treatment option and improve the overall prognosis for R/R-AML patients. This article will review the current treatment status and the latest progress in new drug research of R/R-AML.
    Keywords:  hematopoietic stem cell transplantation ; immunotherapy ; molecular targeted drugs ; relapse and refractory acute myeloid leukemia
    DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2022.06.044
  5. Front Oncol. 2022 ;12 1070514
    Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.
    Ryan S Alden, Mohammad Zahid Kamran, Bassel A Bashjawish, Brittany A Simone.
      Mounting data suggest that cancer cell metabolism can be utilized therapeutically to halt cell proliferation, metastasis and disease progression. Radiation therapy is a critical component of cancer treatment in curative and palliative settings. The use of metabolism-based therapeutics has become increasingly popular in combination with radiotherapy to overcome radioresistance. Over the past year, a focus on glutamine metabolism in the setting of cancer therapy has emerged. In this mini-review, we discuss several important ways (DNA damage repair, oxidative stress, epigenetic modification and immune modulation) glutamine metabolism drives cancer growth and progression, and present data that inhibition of glutamine utilization can lead to radiosensitization in preclinical models. Future research is needed in the clinical realm to determine whether glutamine antagonism is a feasible synergistic therapy that can be combined with radiotherapy.
    Keywords:  cancer; glutamine (Gln); immunotherapy; metabolism; radiation; radiosensitivity; sirpiglenastat; telaglenastat
    DOI:  https://doi.org/10.3389/fonc.2022.1070514
  6. J Control Release. 2022 Dec 06. pii: S0168-3659(22)00817-3. [Epub ahead of print]
    Targeting glycolysis for cancer therapy using drug delivery systems.
    Yongzhuo Huang.
      There is close crosstalk between cancer metabolism and immunity. Cancer metabolism regulation is a promising therapeutic target for cancer immunotherapy. Warburg effect is characterized by abnormal glucose metabolism that includes common features of increased glucose uptake and lactate production. The aerobic glycolysis can reprogram the cancer cells and promote the formation of a suppressive immune microenvironment. As a case in point, lactate plays an essential role in tumorigenesis, which is the end product of glycolysis as well as serves as a fuel supporting cancer cell survival. Meanwhile, it is also an important immune regulator that drives immunosuppression in tumors. Immunometabolic therapy is to intervene tumor metabolism and regulate the related metabolites that participate in the innate and acquired immunity, thereby reinstalling the immune balance and eliciting anticancer immune responses. In this contribution to the Orations - New Horizons of the Journal of controlled Release I will provide an overview of glucose metabolism in tumors and its effects on drug resistance and tumor metastasis, and present the advance of glycolysis-targeting therapy strategies with drug delivery techniques, as well as discuss the challenges in glycolysis-targeting immunometabolic therapy.
    Keywords:  Glycolysis; Immunotherapy; Nanomedicine; Targeted drug delivery; Tumor microenvironment; cancer metabolism
    DOI:  https://doi.org/10.1016/j.jconrel.2022.12.003
  7. Sci Transl Med. 2022 Dec 07. 14(674): eabo6891
    The path to venetoclax resistance is paved with mutations, metabolism, and more.
    Graeme P Sullivan, Lyndsey Flanagan, Daniel Alencar Rodrigues, Tríona Ní Chonghaile.
      Venetoclax is a B cell lymphoma 2 (BCL-2)-selective antagonist used to treat chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). Although this has been a promising therapeutic option for these patients, many of these patients develop resistance and relapsed disease. Here, we summarize the emerging mechanisms of resistance to venetoclax treatment, discuss the promising combination strategies, and highlight the combinations that are currently in clinical trials. Efforts to understand mechanisms of resistance are critical to advance the development of new targeted therapeutic strategies and further our understanding of the biological functions of BCL-2 in tumor cells.
    DOI:  https://doi.org/10.1126/scitranslmed.abo6891
  8. Arch Med Res. 2022 Nov 30. pii: S0188-4409(22)00154-0. [Epub ahead of print]
    Cancer Stem Cells: Biology and Therapeutic Implications.
    Hector Mayani, Antonieta Chávez-González, Karla Vázquez-Santillan, Jorge Contreras, Monica L Guzman.
      It is well recognized that most cancers derive and progress from transformation and clonal expansion of a single cell that possesses stem cell properties, i.e., self-renewal and multilineage differentiation capacities. Such cancer stem cells (CSCs) are usually present at very low frequencies and possess properties that make them key players in tumor development. Indeed, besides having the ability to initiate tumor growth, CSCs drive tumor progression and metastatic dissemination, are resistant to most cancer drugs, and are responsible for cancer relapse. All of these features make CSCs attractive targets for the development of more effective oncologic treatments. In the present review article, we have summarized recent advances in the biology of CSCs, including their identification through their immunophenotype, and their physiology, both in vivo and in vitro. We have also analyzed some molecular markers that might become targets for developing new therapies aiming at hampering CSCs regeneration and cancer relapse.
    Keywords:  Cancer; Leukemia; Microenvironment; Stem cells; Tumor
    DOI:  https://doi.org/10.1016/j.arcmed.2022.11.012
  9. Med Oncol. 2022 Dec 08. 40(1): 44
    GSK3 inhibitor suppresses cell growth and metabolic process in FLT3-ITD leukemia cells.
    Jing Xia, Shuxian Feng, Jian Zhou, Lin Zhang, Dingfang Shi, Mengjie Wang, Yi Zhu, Chaozhi Bu, Daming Xu, Tianyu Li.
      Glycogen Synthase Kinase-3 (GSK-3) was recently implicated in the dysregulated biology of acute myeloid leukemia (AML). Low concentrations of GSK-3 inhibitors, SB216763 and BIO, suppressed the proliferation of AML cells with FLT3-ITD as early as 24 h after treatment. BIO was used in subsequent assays since it exhibited higher inhibitory effects than SB216763. BIO-induced G1 cell cycle arrest by regulating the expression of cyclin D2 and p21 in MV4-11 cells, and promoted apoptosis by regulating the cleaved-caspase3 signaling pathways. In vivo assays demonstrated that BIO suppressed tumor growth, while metabolomics assay showed that BIO reduced the levels of ATP and pyruvate in MV4-11 cells suggesting that it inhibited glycolysis. BIO markedly suppressed cell growth and induced apoptosis of AML cells with FLT3-ITD by partially inhibiting glycolysis, suggesting that BIO may be a promising therapeutic candidate for AML.
    Keywords:  AML; BIO; FLT3; GSK3; Metabolism
    DOI:  https://doi.org/10.1007/s12032-022-01899-2
  10. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2022 Dec;30(6): 1922-1926
    [Research Progress of Cytokines in the Prognosis of Acute Myeloid Leukemia --Review].
    Chun-Yan Liang, Zeng-Zheng Li, Min Wang, Ya-Jie Wang, Tong-Hua Yang.
      At present, acute myeloid leukemia (AML) is mainly treated with combination medication, high-dose, and early intensification. The treatment has achieved good results, but the long-term treatment effect is still not satisfactory. Studies have shown that the different levels of cytokine expression in AML patients can help AML risk stratification, search for treatment directions and predict the prognosis. It has been confirmed that the expression of IL-1β, IL-6, TNF-α, and TGF-β1 are increased in AML patients, and they all indicate a poor prognosis. However, IL-8, IFN-γ, and CCL5 have great research value in chemotherapy resistance and improvement of treatment effect. This article reviews the research progress of cytokine biomarkers in the prognosis of AML patients.
    Keywords:  acute myeloid leukemia ; cytokine ; prognostic factor ; treatment
    DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2022.06.047
  11. Biochem Pharmacol. 2022 Dec 05. pii: S0006-2952(22)00464-6. [Epub ahead of print] 115369
    Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression.
    Srijan Dubey, Sayak Ghosh, Debosmita Goswami, Debapriya Ghatak, Rudranil De.
      Macrophages are specialized immune cells, which have the capacity to phagocytize and destroy the target cells, including tumor cells. Some macrophages, however on their way to devour the cancer cells undergo a change due to a complex set of signaling pathways. They are induced to change into a polarized state known as M2. The M2 macrophages help in metastasis, tumor suppression, and angiogenesis. The macrophage which gets associated with this TME, are referred to as tumor-associated macrophages (TAMs). TAMS undergo a metabolic reprogramming toward oxidative metabolism for bioenergetic purposes (OXPHOS), fatty acid oxidation (FAO), decreased glycolysis, decreased metabolism via the PPP, and upregulation of arginase 1 (ARG1) which triggers immunosuppressive pro-tumor signaling in the tumor microenvironment (TME) in which mitochondria plays an instrumental role. Reports have suggested that a complex series of interactions and exchange of materials, such as cytokines, metabolic intermediates and sometimes even transfer of mitochondria take place between TAMS and other TME components most importantly cancer cells that reprogram their metabolism to encourage cell growth, division, epithelial to mesenchymal transition, that ultimately play an important role in tumor progression. This review will try to focus on the crosstalk between the TAMs with several other components of TME, what instrumental role mitochondria play in that and also try to explore some of the therapeutic options available in cancer patients.
    Keywords:  Macrophage polarization; Mitochondria; Tumor microenvironment; Tumor-Associated Macrophages; cytokines
    DOI:  https://doi.org/10.1016/j.bcp.2022.115369
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