bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–02–19
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Chemoresistance in acute myeloid leukemia: An alternative single-cell RNA sequencing approach.
  2. An Overview: The Diversified Role of Mitochondria in Cancer Metabolism.
  3. Interleukin-34 and immune checkpoint inhibitors: Unified weapons against cancer.
  4. From normal hematopoiesis to malignancies: Highlights from the 2021 Meeting of the Club Hematopoiesis and Oncogenesis.
  5. Targeting mitochondria as a potential therapeutic strategy against chemoresistance in cancer.
  6. Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) overcomes adaptive drug resistance in acute myelogenous leukemia.
  7. Influenced tumor microenvironment and tumor immunity by amino acids.
  8. Hematopoietic Stem Cell Aging and Leukemia Transformation.
  1. Hematol Oncol. 2023 Feb 15.
    Chemoresistance in acute myeloid leukemia: An alternative single-cell RNA sequencing approach.
    Po-Liang Cheng, Tzu-Hung Hsiao, Chung-Hsing Chen, Miao-Neng Hung, Pei-Pei Jhan, Li-Wen Lee, Ting-Shuan Wu, Jia-Rung Tsai, Chieh-Lin Jerry Teng.
      Our previous study demonstrated that myc, mitochondrial oxidative phosphorylation, mTOR, and stemness are independently responsible for chemoresistance in acute myeloid leukemia (AML) cells. This study aimed to identify potential mechanisms of chemoresistance of the "7+3" induction in AML by using a single-cell RNA sequencing (scRNA-seq) approach. In the present study, 13 untreated patients with de novo AML were enrolled and stratified into two groups: complete remission (CR; n = 8) and non-CR (n = 5). scRNA-seq was used to analyze genetic profiles of 28,950 AML cells from these patients; results were validated using a previously published bulk RNA-seq dataset. Our study results showed chemoresistant AML cells had premature accumulation during early hematopoiesis. Hematopoietic stem cell-like cells from the non-CR group expressed more leukemic stem cell markers (CD9, CD82, IL3RA, and IL1RAP) than those from the CR group. Chemoresistant progenitor cells had impaired myeloid differentiation owing to early arrest of hematopoiesis. Notably, AML cells analyzed by scRNA-seq and bulk RNA-seq harbored a comparable myeloid lineage cell fraction, which internally validated our results. Using the TCGA database, our analysis demonstrated that patients with AML with higher expression of chemoresistant genetic markers (IL3RA and IL1RAP) had a worse overall survival (p< 0.01 for IL3RA; p< 0.05 for IL1RAP). In conclusion, AML cells responsive and resistant to the "7 + 3" induction were derived from a diverse cancerous hematopoietic stem cell population, as indicated by the specific genetic biomarkers obtained using scRNA-seq approach. Furthermore, arrest of hematopoiesis was shown to occur earlier in chemoresistant AML cells, furthering the current understanding of chemoresistance in AML. This article is protected by copyright. All rights reserved.
    Keywords:  Single-cell RNA-seq; acute myeloid leukemia; chemoresistance; leukemia stem cells
    DOI:  https://doi.org/10.1002/hon.3129
  2. Int J Biol Sci. 2023 ;19(3): 897-915
    An Overview: The Diversified Role of Mitochondria in Cancer Metabolism.
    Yu'e Liu, Yihong Sun, Yadong Guo, Xiaoyun Shi, Xi Chen, Wenfeng Feng, Lei-Lei Wu, Jin Zhang, Shibo Yu, Yi Wang, Yufeng Shi.
      Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD+/NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.
    Keywords:  cancer; mitochondria; tumor metabolism; tumor metastasis
    DOI:  https://doi.org/10.7150/ijbs.81609
  3. Front Oncol. 2023 ;13 1099696
    Interleukin-34 and immune checkpoint inhibitors: Unified weapons against cancer.
    Fadhl Alshaebi, Mohammed Safi, Yousif A Algabri, Mahmoud Al-Azab, Abdullah Aldanakh, Mohammed Alradhi, Alariqi Reem, Caiqing Zhang.
      Interleukin-34 (IL-34) is a cytokine that is involved in the regulation of immune cells, including macrophages, in the tumor microenvironment (TME). Macrophages are a type of immune cell that can be found in large numbers within the TME and have been shown to have a role in the suppression of immune responses in cancer. This mmune suppression can contribute to cancer development and tumors' ability to evade the immune system. Immune checkpoint inhibitors (ICIs) are a type of cancer treatment that target proteins on immune cells that act as "checkpoints," regulating the activity of the immune system. Examples of these proteins include programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). ICIs work by blocking the activity of these proteins, allowing the immune system to mount a stronger response against cancer cells. The combination of IL-34 inhibition with ICIs has been proposed as a potential treatment option for cancer due to the role of IL-34 in the TME and its potential involvement in resistance to ICIs. Inhibiting the activity of IL-34 or targeting its signaling pathways may help to overcome resistance to ICIs and improve the effectiveness of these therapies. This review summarizes the current state of knowledge concerning the involvement of IL-34-mediated regulation of TME and the promotion of ICI resistance. Besides, this work may shed light on whether targeting IL-34 might be exploited as a potential treatment option for cancer patients in the future. However, further research is needed to fully understand the mechanisms underlying the role of IL-34 in TME and to determine the safety and efficacy of this approach in cancer patients.
    Keywords:  cancer therapy; cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); immune checkpoint inhibitors (ICIs); interluikin-34 (IL-34); programmed cell death protein 1 (PD-1); tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1099696
  4. Bull Cancer. 2023 Feb 10. pii: S0007-4551(23)00039-5. [Epub ahead of print]
    From normal hematopoiesis to malignancies: Highlights from the 2021 Meeting of the Club Hematopoiesis and Oncogenesis.
    Marie-Bérengère Troadec, Françoise Porteu, Marie-Laure Arcangeli, Adlen Foudi, Dominique Bluteau, Paulo De Sepulveda, Christel Guillouf, Nathalie M Mazure, Fabienne Meggetto, Philippe Brunet De La Grange, Cyril Broccardo.
      This article highlights the presentations from the 2021 scientific meeting of the Club Hematopoiesis and Oncogenesis. This annual meeting focuses on hematopoiesis and oncogenic mechanisms. Various topics were presented: expansion of hematopoietic stem cells with in vivo and ex vivo strategies, the role of the hematopoietic stem cell niches in aging and leukemic resistance, the crossroad between hematology and immunology, the importance of the metabolism in normal hematopoiesis and hematopoietic defects, solid tumors and oncogenesis, the noncoding genome, inflammation in monocyte differentiation and leukemia, and importantly, the recent advances in myeloid malignancies, lymphoid leukemia and lymphoma.
    Keywords:  Hematopoiesis; Immunity; Inflammation; Leukemia; Metabolism; Myelodysplasia; Oncogenesis
    DOI:  https://doi.org/10.1016/j.bulcan.2022.12.013
  5. Biomed Pharmacother. 2023 Feb 09. pii: S0753-3322(23)00186-5. [Epub ahead of print]160 114398
    Targeting mitochondria as a potential therapeutic strategy against chemoresistance in cancer.
    Soumi Mukherjee, Gurjit Kaur Bhatti, Ravindresh Chhabra, P Hemachandra Reddy, Jasvinder Singh Bhatti.
      The importance of mitochondria is not only limited to energy generation but also in several physical and chemical processes critical for cell survival. Mitochondria play an essential role in cellular apoptosis, calcium ion transport and cellular metabolism. Mutation in the nuclear and mitochondrial genes, altered oncogenes/tumor suppressor genes, and deregulated signalling for cell viability are major reasons for cancer progression and chemoresistance. The development of drug resistance in cancer patients is a major challenge in cancer treatment as the resistant cells are often more aggressive. The drug resistant cells of numerous cancer types exhibit the deregulation of mitochondrial function. The increased biogenesis of mitochondria and its dynamic alteration contribute to developing resistance. Further, a small subpopulation of cancer stem cells in the heterogeneous tumor is primarily responsible for chemoresistance and has an attribute of mitochondrial dysfunction. This review highlights the critical role of mitochondrial dysfunction in chemoresistance in cancer cells through the processes of apoptosis, autophagy/mitophagy, and cancer stemness. Mitochondria-targeted therapeutic strategies might help reduce cancer progression and chemoresistance induced by various cancer drugs.
    Keywords:  Apoptosis, Autophagy; Cancer chemoresistance; Mitochondrial biogenesis, Stemness; Mitochondrial dynamics; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.biopha.2023.114398
  6. Mol Cancer Res. 2023 Feb 14. pii: MCR-22-0343. [Epub ahead of print]
    Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) overcomes adaptive drug resistance in acute myelogenous leukemia.
    Seemana Bhattacharya, Sujan Piya, Huaxian Ma, Priyanka Sharma, Qi Zhang, Natalia Baran, Vivian R Ruvolo, Teresa McQueen, R Eric Davis, Rasoul Pourebrahim, Marina Konopleva, Hagop Kantarjian, Nicholas D P Cosford, Michael Andreeff, Gautam Borthakur.
      Despite effective new therapies, adaptive resistance remains the main obstacle in AML therapy. Autophagy induction is a key mechanism for adaptive resistance. Leukemic blasts at diagnosis express higher levels of the apical autophagy kinase ULK1 compared to normal hematopoietic cells. Exposure to chemotherapy and targeted agents upregulate ULK1, hence we hypothesize that developing ULK1 inhibitors may present the unique opportunity for clinical translation of autophagy inhibition. Accordingly, we demonstrate that ULK1 inhibition, by genetic and pharmacological means, suppresses treatment-induced autophagy, overcomes adaptive drug-resistance, and synergizes with chemotherapy and emerging anti-leukemia agents like venetoclax (ABT-199). The study next aims at exploring the underlying mechanisms. Mechanistically, ULK1 inhibition downregulates MCL1 anti-apoptotic gene, impairs mitochondrial function and downregulates components of the CD44-xCT system, resulting in impaired reactive oxygen species (ROS) mitigation, DNA damage and apoptosis. For further validation, several mouse models of AML were generated. In these mouse models, ULK1 deficiency impaired leukemic cell homing and engraftment, delayed disease progression and improved survival. Therefore, in the study we validated our hypothesis and identified ULK1 as an important mediator of adaptive resistance to therapy and an ideal candidate for combination therapy in AML. Therefore, we propose ULK1 inhibition as a therapeutically relevant treatment option to overcome adaptive drug-resistance in AML. Implications: ULK1 drives a cell-intrinsic adaptive resistance in AML and targeting ULK1 mediated autophagy can synergize with existing and emerging AML therapies to overcome drug-resistance and induce apoptosis.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0343
  7. Front Immunol. 2023 ;14 1118448
    Influenced tumor microenvironment and tumor immunity by amino acids.
    Min Yu, Shuang Zhang.
      It is widely accepted that tumors are a complex tissue composed of cancer cells, extracellular matrix, inflammatory cells, immune cells, and other cells. Deregulation of tumor microenvironment promotes tumor aggressiveness by sustaining cell growth, invasion, and survival from immune surveillance. The concepts that some dietary nutrients could change tumor microenvironment are extremely attractive. Many studies demonstrated that high-fat diet-induced obesity shaped metabolism to suppress anti-tumor immunity, but how amino acids changed the tumor microenvironment and impacted tumor immunity was still not totally understood. In fact, amino acid metabolism in different signaling pathways and their cross-talk shaped tumor immunity and therapy efficacy in cancer patients. Our review focused on mechanisms by which amino acid influenced tumor microenvironment, and found potential drug targets for immunotherapy in cancer.
    Keywords:  T lymphocytes; amino acids; cancer cells; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1118448
  8. Blood. 2023 Feb 17. pii: blood.2022017933. [Epub ahead of print]
    Hematopoietic Stem Cell Aging and Leukemia Transformation.
    Patricia A Colom Díaz, Jayna J Mistry, Jennifer J Trowbridge.
      With aging, hematopoietic stem cells (HSCs) have an impaired ability to regenerate, differentiate, and produce the entire repertoire of mature blood and immune cells. Due to dysfunctional hematopoiesis, the incidence of hematologic malignancies increases in elderly individuals. Here, we provide an update on HSC-intrinsic and HSC-extrinsic factors and processes recently discovered to contribute to functional decline of HSCs during aging. In addition, we discuss targets and timing of intervention approaches to maintain HSC function during aging and the extent to which these same targets may prevent or delay transformation to hematologic malignancies.
    DOI:  https://doi.org/10.1182/blood.2022017933
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