bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–11–20
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Editorial: Characteristics and behaviors of hematopoietic stem cells and leukemia stem cells in hematologic malignancies.
  2. Editorial: Novel mechanisms for the treatment of AML before and after transplant.
  3. Bispecific antibody-targeted T-cell therapy for acute myeloid leukemia.
  4. α-ketoglutarate suppresses immediate early gene expression in cancer cells.
  5. Engaging stemness improves cancer immunotherapy.
  6. Targeting lipid metabolism for ferroptotic cancer therapy.
  7. Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia.
  8. Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis.
  9. New insights into epigenetic regulation of resistance to PD-1/PD-L1 blockade cancer immunotherapy: mechanisms and therapeutic opportunities.
  10. Immunometabolism in the tumor microenvironment and its related research progress.
  1. Front Oncol. 2022 ;12 1037202
    Editorial: Characteristics and behaviors of hematopoietic stem cells and leukemia stem cells in hematologic malignancies.
    Haojian Zhang, Pengxu Qian.
      
    Keywords:  acute myeloid leukemia; chronic myeloid leukemia; drug resistance; hematopoietic malignancies; hematopoietic stem cell; leukemia stem cell
    DOI:  https://doi.org/10.3389/fonc.2022.1037202
  2. Front Oncol. 2022 ;12 1063307
    Editorial: Novel mechanisms for the treatment of AML before and after transplant.
    Margaret T Kasner.
      
    Keywords:  AML - acute myeloid leukemia; Maintenance therapy; allogeneic stem cell transplantation; novel therapeutic agents; targeted agents
    DOI:  https://doi.org/10.3389/fonc.2022.1063307
  3. Front Immunol. 2022 ;13 899468
    Bispecific antibody-targeted T-cell therapy for acute myeloid leukemia.
    Ewa Kubicka, Lawrence G Lum, Manley Huang, Archana Thakur.
      The management of relapsed or refractory acute myeloid leukemia (AML) continues to be therapeutically challenging. Non-toxic immunotherapy approaches are needed to provide long-term anti-leukemic effects. The goal of this study was to determine whether activated T cells (ATCs) armed with bispecific antibodies (BiAbs) could target and lyse leukemic and leukemic stem cells (LSCs). Anti-CD3 × anti-CD123 BiAb (CD123Bi) and anti-CD3 × anti-CD33GO (gemtuzumab ozogamicin [GO]) BiAb (CD33GOBi) were used to arm ATCs to produce bispecific antibody armed activated T cells (designated CD123 BATs or CD33GO BATs) to target AML cell lines, peripheral blood mononuclear cells from AML patients, and in vivo treatment of AML in xenogeneic NSG mice engrafted with leukemic cells. BATs exhibited high levels of specific cytotoxicity directed at AML cell lines at low 1:1 or 1:2 effector-to-target (E:T) ratios and secrete Th1 cytokines upon target engagement. In vivo study in AML-engrafted NSG mice showed significantly prolonged survival in mice treated with CD33GO BATs (p < 0.0001) or CD123 BATs (p < 0.0089) compared to ATC-treated control mice. Patient samples containing leukemic blasts and LSCs when treated with CD33GO BATs or CD123 BATs for 18 h showed a significant reduction (50%-100%; p < 0.005) in blasts and 75%-100% reduction in LSCs (p < 0.005) in most cases compared to unarmed ATCs. This approach may provide a potent and non-toxic strategy to target AML blasts and LSCs and enhance chemo-responsiveness in older patients who are likely to develop recurrent diseases.
    Keywords:  acute myeloid leukemia; anti-CD123; anti-CD33; bispecific antibodies; targeted T cells
    DOI:  https://doi.org/10.3389/fimmu.2022.899468
  4. Biochem Biophys Res Commun. 2022 Nov 11. pii: S0006-291X(22)01562-5. [Epub ahead of print]637 144-152
    α-ketoglutarate suppresses immediate early gene expression in cancer cells.
    Sungmin Joo, Seungwoo Baek, Jaehyeon Kang, Dong Soo Seo, Taeg Kyu Kwon, Younghoon Jang.
      Cancer cells exhibit increased glutamine consumption compared to normal cells, supporting cell survival and proliferation. Glutamine is converted to α-ketoglutarate (αKG), which then enters the tricarboxylic acid cycle to generate ATP. Recently, therapeutic modulation of glutamine metabolism has become an attractive metabolic anti-cancer strategy. However, how synergistic combination therapy is required to overcome glutamine metabolism drug resistance remains elusive. To address this issue, we first investigated the role of αKG in regulating gene expression in several cancer cell lines. Using RNA-seq analysis and histone modification screening, we demonstrated that αKG reduced the expression of the immediate early gene (IEG) in cancer cells in an H3K27 acetylation-dependent manner. Conversely, glutaminase (GLS) inhibitors induce IEG expression in cancer cells. Furthermore, we showed that siRNA knockdown of orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) induces IEG expression. Notably, the NR4A1 agonist cytosporone B sensitizes GLS inhibitor resistance to cancer cell death. Together, these findings indicate that therapeutic targeting of IEG dysregulation by αKG can be a potentially effective anti-cancer therapeutic strategy for glutamine metabolism inhibitors.
    Keywords:  Cancer cells; GLS inhibitor; IEG; NR4A; αKG
    DOI:  https://doi.org/10.1016/j.bbrc.2022.11.021
  5. Cancer Lett. 2022 Nov 14. pii: S0304-3835(22)00494-3. [Epub ahead of print] 216007
    Engaging stemness improves cancer immunotherapy.
    Hassan Dianat-Moghadam, Mohammadreza Sharifi, Rasoul Salehi, Mohsen Keshavarz, Mehdi Shahgolzari, Zohreh Amoozgar.
      Intra-tumoral immune cells promote the stemness of cancer stem cells (CSCs) in the tumor microenvironment (TME). CSCs promote tumor progression, relapse, and resistance to immunotherapy. Cancer stemness induces the expression of neoantigens and neo-properties in CSCs, creating an opportunity for targeted immunotherapies. Isolation of stem-like T cells or retaining stemness in T clonotypes strategies produces exhaustion-resistance T cells with superior re-expansion capacity and long-lasting responses after adoptive cell therapies. Stem cells-derived NK cells may be the next generation of NK cell products for immunotherapy. Here, we have reviewed mechanisms by which stemness factors modulated the immunoediting of the TME and summarized the potentials of CSCs in the development of immunotherapy regimens, including CAR-T cells, CAR-NK cells, cancer vaccines, and monoclonal antibodies. We have discussed the natural or genetically engineered stem-like T cells and stem cell-derived NK cells with increased cytotoxicity to tumor cells. Finally, we have provided a perspective on approaches that may improve the therapeutic efficacy of these novel adoptive cell-based products in targeting immunosuppressive TME.
    Keywords:  Adoptive cell therapy; CAR-NK cell; Cancer stem cell; Neoantigens; Stem-like T cell
    DOI:  https://doi.org/10.1016/j.canlet.2022.216007
  6. Apoptosis. 2022 Nov 18.
    Targeting lipid metabolism for ferroptotic cancer therapy.
    Minhua Luo, Jiajing Yan, Xinyu Hu, Haolong Li, Hongsheng Li, Quentin Liu, Yibing Chen, Zhengzhi Zou.
      It has been 10 years since the concept of ferroptosis was put forward and research focusing on ferroptosis has been increasing continuously. Ferroptosis is driven by iron-dependent lipid peroxidation, which can be antagonized by glutathione peroxidase 4 (GPX4), ferroptosis inhibitory protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH) and Fas-associated factor 1 (FAF1). Various cellular metabolic events, including lipid metabolism, can modulate ferroptosis sensitivity. It is worth noting that the reprogramming of lipid metabolism in cancer cells can promote the occurrence and development of tumors. The metabolic flexibility of cancer cells opens the possibility for the coordinated targeting of multiple lipid metabolic pathways to trigger cancer cells ferroptosis. In addition, cancer cells must obtain immortality, escape from programmed cell death including ferroptosis, to promote cancer progression, which provides new perspectives for improving cancer therapy. Targeting the vulnerability of ferroptosis has received attention as one of the significant possible strategies to treat cancer given its role in regulating tumor cell survival. We review the impact of iron and lipid metabolism on ferroptosis and the potential role of the crosstalk of lipid metabolism reprogramming and ferroptosis in antitumor immunity and sum up agents targeting lipid metabolism and ferroptosis for cancer therapy.
    Keywords:  Anti-tumor immunity; Ferroptosis; Ferroptotic cancer therapy; Lipid metabolism
    DOI:  https://doi.org/10.1007/s10495-022-01795-0
  7. Leukemia. 2022 Nov 18.
    Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia.
    Victoria Y Ling, Jasmin Straube, William Godfrey, Rohit Haldar, Yashaswini Janardhanan, Leanne Cooper, Claudia Bruedigam, Emily Cooper, Paniz Tavakoli Shirazi, Sebastien Jacquelin, Siok-Keen Tey, Jonathan Baell, Fei Huang, Jianwen Jin, Yichao Zhao, Lars Bullinger, Megan J Bywater, Steven W Lane.
      Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G1S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.
    DOI:  https://doi.org/10.1038/s41375-022-01755-2
  8. Front Oncol. 2022 ;12 981406
    Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis.
    Ruiqi Jiang, Mingnan Cao, Shenghui Mei, Shanshan Guo, Wei Zhang, Nan Ji, Zhigang Zhao.
       Background: Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. Since Warburg O first observed alterations in cancer metabolism in the 1950s, people gradually found tumor metabolism pathways play a fundamental role in regulating the response to chemotherapeutic drugs, and the attempts of targeting tumor energetics have shown promising preclinical outcomes in recent years. This study aimed to summarize the knowledge structure and identify emerging trends and potential hotspots in metabolic signaling pathways of tumor drug resistance research.
    Methods: Publications related to metabolic signaling pathways of tumor drug resistance published from 1992 to 2022 were retrieved from the Web of Science Core Collection database. The document type was set to articles or reviews with language restriction to English. Two different scientometric software including Citespace and VOS viewer were used to conduct this scientometric analysis.
    Results: A total of 2,537 publications including 1,704 articles and 833 reviews were retrieved in the final analysis. The USA made the most contributions to this field. The leading institution was the University of Texas MD Anderson Cancer Center. Avan A was the most productive author, and Hanahan D was the key researcher with the most co-citations, but there is no leader in this field yet. Cancers was the most influential academic journal, and Oncology was the most popular research field. Based on keywords occurrence analysis, these selected keywords could be roughly divided into five main topics: cluster 1 (study of cancer cell apoptosis pathway); cluster 2 (study of resistance mechanisms of different cancer types); cluster 3 (study of cancer stem cells); cluster 4 (study of tumor oxidative stress and inflammation signaling pathways); and cluster 5 (study of autophagy). The keywords burst detection identified several keywords as new research hotspots, including "tumor microenvironment," "invasion," and "target".
    Conclusion: Tumor metabolic reprogramming of drug resistance research is advancing rapidly. This study serves as a starting point, providing a thorough overview, the development landscape, and future opportunities in this field.
    Keywords:  drug resistance; metabolism; scientometrics; signaling pathways; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.981406
  9. Exp Hematol Oncol. 2022 Nov 16. 11(1): 101
    New insights into epigenetic regulation of resistance to PD-1/PD-L1 blockade cancer immunotherapy: mechanisms and therapeutic opportunities.
    Mengyuan Dai, Miao Liu, Hua Yang, Can Küçük, Hua You.
      Programmed cell death protein 1(PD-1) is a type of immune-inhibitory checkpoint protein, which delivers inhibitory signals to cytotoxic T cells by binding to the programmed death ligand-1 (PD-L1) displayed on the surface of cancer cells. Antibodies blocking PD-1/PD-L1 interaction have been extensively used in treatment of human malignancies and have achieved promising outcomes in recent years. However, gradual development of resistance to PD-1/PD-L1 blockade has decreased the effectiveness of this immunotherapy in cancer patients. The underlying epigenetic mechanisms need to be elucidated for application of novel strategies overcoming this immunotherapy resistance. Epigenetic aberrations contribute to cancerogenesis by promoting different hallmarks of cancer. Moreover, these alterations may lead to therapy resistance, thereby leading to poor prognosis. Recently, the epigenetic regulatory drugs have been shown to decrease the resistance to PD-1/PD-L1 inhibitors in certain cancer patients. Inhibitors of the non-coding RNAs, DNA methyltransferases, and histone deacetylases combined with PD-1/PD-L1 inhibitors have shown considerable therapeutic efficacy against carcinomas as well as blood cancers. Importantly, DNA methylation-mediated epigenetic silencing can inhibit antigen processing and presentation, which promotes cancerogenesis and aggravates resistance to PD-1/PD-L1 blockade immunotherapy. These observations altogether suggest that the combination of the epigenetic regulatory drugs with PD-1/PD-L1 inhibitors may present potential solution to the resistance caused by monotherapy of PD-1/PD-L1 immunotherapy.
    Keywords:  DNA methyltransferase; Epigenetic regulation; Histone deacetylase; Immune checkpoints; Non-coding RNA; PD-1/PD-L1; Therapy resistance
    DOI:  https://doi.org/10.1186/s40164-022-00356-0
  10. Front Oncol. 2022 ;12 1024789
    Immunometabolism in the tumor microenvironment and its related research progress.
    Ziheng Zhang, Yajun Hu, Yuefeng Chen, Zhuoneng Chen, Yexin Zhu, Mingmin Chen, Jichu Xia, Yixuan Sun, Wenfang Xu.
      The tumor immune microenvironment has been a research hot spot in recent years. The cytokines and metabolites in the microenvironment can promote the occurrence and development of tumor in various ways and help tumor cells get rid of the surveillance of the immune system and complete immune escape. Many studies have shown that the existence of tumor microenvironment is an important reason for the failure of immunotherapy. The impact of the tumor microenvironment on tumor is a systematic study. The current research on this aspect may be only the tip of the iceberg, and a relative lack of integrity, may be related to the heterogeneity of tumor. This review mainly discusses the current status of glucose metabolism and lipid metabolism in the tumor microenvironment, including the phenotype of glucose metabolism and lipid metabolism in the microenvironment; the effects of these metabolic methods and their metabolites on three important immune cells Impact: regulatory T cells (Tregs), tumor-associated macrophages (TAM), natural killer cells (NK cells); and the impact of metabolism in the targeted microenvironment on immunotherapy. At the end of this article,the potential relationship between Ferroptosis and the tumor microenvironment in recent years is also briefly described.
    Keywords:  NK cells; Tregs; glucose metabolism; lipid metabolism; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1024789
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