bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–12–25
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Upregulation of Tim-3 is associated with poor prognosis in acute myeloid leukemia.
  2. Leukemic stem cells and advances in hematopoietic stem cell transplantation for acute myeloid leukemia: a narrative review of clinical trials.
  3. Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets.
  4. Revisiting the Warburg Effect with Focus on Lactate.
  5. Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines.
  6. Construction and validation of a fatty acid metabolism risk signature for predicting prognosis in acute myeloid leukemia.
  7. Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis.
  8. Editorial: Women in cancer metabolism: 2021/2022.
  9. Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML.
  10. Mitochondria Drive Immune Responses in Critical Disease.
  11. Evaluating the prognostic value of CD56 in pediatric acute myeloid leukemia.
  12. Moms' mitochondria may refresh cells in sick kids.
  1. Cancer Med. 2022 Dec 21.
    Upregulation of Tim-3 is associated with poor prognosis in acute myeloid leukemia.
    Zhengwei Wu, Jiawang Ou, Nannan Liu, Zhixiang Wang, Junjie Chen, Zihong Cai, Xiaoli Liu, Xiao Yu, Min Dai, Hongsheng Zhou.
      Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy originated from leukemia stem cells (LSC). Emerging evidence suggests T-cell immunoglobulin mucin-3(Tim3) as surface marker for LSC. However, the clinical significance and biology of Tim-3 in AML remain to be determined, especially those LSCs. In public AML databases as well as our data, we separated AML patients into Tim-3high and Tim-3low subsets using the X-tile software and evaluated the associations between Tim-3 and overall survival (OS) and disease-free survival (DFS). The Cancer Genome Atlas (TCGA) cohort revealed that high Tim-3 expression in leukemic cells was linked with poor prognosis (DFS: p = 0.018; OS: p = 0.041). Furthermore, multiple regression analysis shows that Tim-3 was an independent factor for the prognosis (HR = 2.26, 95% CI = 1.15-4.44, p = 0.017). Validation cohort of public gene expression omnibus (GEO) confirmed that Tim-3 was a prognostic candidate in AML. Besides, in our internal cohort, we also confirmed that over expression of Tim-3 protein in LSC/LPC made poor prognosis in AML. Additionally, we revealed that the LSC markers AKR1C3, CD34, and MMRN1 were upregulated in the Tim-3high group of TCGA. We found that the upregulated genes in the Tim-3high group were mainly enriched in immune response, cytokine binding and cell adhesion molecules, and JAK-STAT signaling pathway, by gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Collectively, we revealed that, for the first time, upregulation of Tim-3 in LSCs at the level of gene and protein expression is associated with poor prognosis and the important biological feature of Tim-3 of LSC in AML.
    Keywords:  T-cell immunoglobulin mucin 3; acute myeloid leukemia; immune response; leukemia stem cell; prognosis
    DOI:  https://doi.org/10.1002/cam4.5549
  2. Stem Cell Investig. 2022 ;9 10
    Leukemic stem cells and advances in hematopoietic stem cell transplantation for acute myeloid leukemia: a narrative review of clinical trials.
    Vikram Sumbly, Ian Landry, Christina Sneed, Qamar Iqbal, Anu Verma, Tenzin Dhokhar, Adeel Masood, Akshay Amaraneni.
       Objective: The purpose of this literature review is to summarize and provide a brief overview of our current understanding of acute myeloid leukemia (AML) and the role of stem cell transplantation (SCT) in its management.
    Background: AML is a malignant hematological disorder that is characterized by the uncontrolled proliferation of myeloid blood cells. This disease has been associated with various risk factors such as ionizing radiation, cigarette smoke, pesticides/herbicides, and chemotherapy. SCT remains the most beneficial treatment for medically fit AML patients due to superior survival outcomes.
    Methods: A thorough search was conducted on PubMed, Scopus, ClinicalTrials.gov, Embase and Web of Science using related keywords. Current articles on the uses of stem cell therapy in AML patients were selected.
    Conclusions: Long term exposure to ionizing radiation and other harmful substances such as benzene, cigarette smoke and chemotherapeutic drugs plays an important role in AML carcinogenesis. Mutations in certain genes (e.g., ASXL1, RUNX1, KIT, TP53, BCR-ABL1) seem to accelerate the process as they affect normal cellular proliferation and cell death. These events may give rise to a small subpopulation of leukemic stem cells (LSC) which continuously sustain tumor development and growth. Patients who are deemed to be medically "fit" should receive an allogenic hematopoietic stem cell transplantation (allo-HSCT) due to improved overall survival (OS) (~50%) and decreased relapsed risk (32% vs. 59%). Several studies have revealed that the medically "unfit" may benefit from more conventional agents such as azacytidine, decitabine, venetoclax or sorafenib.
    Keywords:  Cancer stem cells (CSC); acute myeloid leukemia (AML); malignant hematology; stem cell transplantation (SCT)
    DOI:  https://doi.org/10.21037/sci-2022-044
  3. Blood. 2022 Dec 22. pii: blood.2022018092. [Epub ahead of print]
    Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets.
    Sushanta Kumar Mishra, Scott Evan Millman, Lingbo Zhang.
      Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemia cells is often genotype-specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML, explores the role of key vitamins and enzymes that regulate these processes, and provides an overview of metabolism-directed therapies currently in use or development.
    DOI:  https://doi.org/10.1182/blood.2022018092
  4. Cancers (Basel). 2022 Dec 07. pii: 6028. [Epub ahead of print]14(24):
    Revisiting the Warburg Effect with Focus on Lactate.
    Eva Kocianova, Viktoria Piatrikova, Tereza Golias.
      Rewired metabolism is acknowledged as one of the drivers of tumor growth. As a result, aerobic glycolysis, or the Warburg effect, is a feature of many cancers. Increased glucose uptake and glycolysis provide intermediates for anabolic reactions necessary for cancer cell proliferation while contributing sufficient energy. However, the accompanying increased lactate production, seemingly wasting glucose carbon, was originally explained only by the need to regenerate NAD+ for successive rounds of glycolysis by the lactate dehydrogenase (LDH) reaction in the cytosol. After the discovery of a mitochondrial LDH isoform, lactate oxidation entered the picture, and lactate was recognized as an important oxidative fuel. It has also been revealed that lactate serves a variety of signaling functions and helps cells adapt to the new environment. Here, we discuss recent findings on lactate metabolism and signaling in cancer while attempting to explain why the Warburg effect is adopted by cancer cells.
    Keywords:  Warburg effect; glucose metabolism; lactate; lactate dehydrogenase; lactate oxidation; lactate shuttle; lactate signaling; lactylation
    DOI:  https://doi.org/10.3390/cancers14246028
  5. Front Oncol. 2022 ;12 1032336
    Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines.
    Rafael Renatino Canevarolo, Carolina Pereira de Souza Melo, Nathalia Moreno Cury, Leonardo Luiz Artico, Juliana Ronchi Corrêa, Yanca Tonhasca Lau, Samara Sousa Mariano, Praneeth Reddy Sudalagunta, Silvia Regina Brandalise, Ana Carolina de Mattos Zeri, José Andrés Yunes.
       Introduction: Methotrexate (MTX), a folic acid antagonist and nucleotide synthesis inhibitor, is a cornerstone drug used against acute lymphoblastic leukemia (ALL), but its mechanism of action and resistance continues to be unraveled even after decades of clinical use.
    Methods: To better understand the mechanisms of this drug, we accessed the intracellular metabolic content of 13 ALL cell lines treated with MTX by 1H-NMR, and correlated metabolome data with cell proliferation and gene expression. Further, we validated these findings by inhibiting the cellular antioxidant system of the cells in vitro and in vivo in the presence of MTX.
    Results: MTX altered the concentration of 31 out of 70 metabolites analyzed, suggesting inhibition of the glycine cleavage system, the pentose phosphate pathway, purine and pyrimidine synthesis, phospholipid metabolism, and bile acid uptake. We found that glutathione (GSH) levels were associated with MTX resistance in both treated and untreated cells, suggesting a new constitutive metabolic-based mechanism of resistance to the drug. Gene expression analyses showed that eight genes involved in GSH metabolism were correlated to GSH concentrations, 2 of which (gamma-glutamyltransferase 1 [GGT1] and thioredoxin reductase 3 [TXNRD3]) were also correlated to MTX resistance. Gene set enrichment analysis (GSEA) confirmed the association between GSH metabolism and MTX resistance. Pharmacological inhibition or stimulation of the main antioxidant systems of the cell, GSH and thioredoxin, confirmed their importance in MTX resistance. Arsenic trioxide (ATO), a thioredoxin inhibitor used against acute promyelocytic leukemia, potentiated MTX cytotoxicity in vitro in some of the ALL cell lines tested. Likewise, the ATO+MTX combination decreased tumor burden and extended the survival of NOD scid gamma (NSG) mice transplanted with patient-derived ALL xenograft, but only in one of four ALLs tested.
    Conclusion: Altogether, our results show that the cellular antioxidant defense systems contribute to leukemia resistance to MTX, and targeting these pathways, especially the thioredoxin antioxidant system, may be a promising strategy for resensitizing ALL to MTX.
    Keywords:  acute lymphoblastic leukemia; arsenic trioxide; drug resistance; glutathione; metabolomics; methotrexate; thioredoxin reductase
    DOI:  https://doi.org/10.3389/fonc.2022.1032336
  6. BMC Genom Data. 2022 Dec 22. 23(1): 85
    Construction and validation of a fatty acid metabolism risk signature for predicting prognosis in acute myeloid leukemia.
    Miao Chen, Yuan Tao, Pengjie Yue, Feng Guo, Xiaojing Yan.
       BACKGROUND: Fatty acid metabolism has been reported to play important roles in the development of acute myeloid leukemia (AML), but there are no prognostic signatures composed of fatty acid metabolism-related genes. As the current prognostic evaluation system has limitations due to the heterogeneity of AML patients, it is necessary to develop a new signature based on fatty acid metabolism to better guide prognosis prediction and treatment selection.
    METHODS: We analyzed the RNA sequencing and clinical data of The Cancer Genome Atlas (TCGA) and Vizome cohorts. The analyses were performed with GraphPad 7, the R language and SPSS.
    RESULTS: We selected nine significant genes in the fatty acid metabolism gene set through univariate Cox analysis and the log-rank test. Then, a fatty acid metabolism signature was established based on these genes. We found that the signature was as an independent unfavourable prognostic factor and increased the precision of prediction when combined with classic factors in a nomogram. Gene Ontology (GO) and gene set enrichment analysis (GSEA) showed that the risk signature was closely associated with mitochondrial metabolism and that the high-risk group had an enhanced immune response.
    CONCLUSION: The fatty acid metabolism signature is a new independent factor for predicting the clinical outcomes of AML patients.
    Keywords:  Acute myeloid leukemia; Fatty acid metabolism; Mitochondrial metabolism; Prognostic signature
    DOI:  https://doi.org/10.1186/s12863-022-01099-x
  7. Mol Cancer. 2022 Dec 22. 21(1): 225
    Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis.
    Palanisamy Nallasamy, Rama Krishna Nimmakayala, Seema Parte, Abhirup C Are, Surinder K Batra, Moorthy P Ponnusamy.
      Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of cancer cells. The correlation between TME and CSCs remains an enigma in understanding the events of metastasis and therapy resistance in cancer biology. Recent evidence suggests that TME dictates the CSCs maintenance to arbitrate cancer progression and metastasis. The immune, inflammatory, endothelial, adipocyte, and fibroblast cells in the TME release growth factors, cytokines, chemokines, microRNAs, and exosomes that provide cues for the gain and maintenance of CSC features. These intricate cross-talks are fueled to evolve into aggressive, invasive, migratory phenotypes for cancer development. In this review, we have abridged the recent developments in the role of the TME factors in CSC maintenance and how these events influence the transition of tumor progression to further translate into metastasis and therapy resistance in cancer.
    Keywords:  Cancer stem cells; Fibroblasts; Metastatic stem cells; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-022-01682-x
  8. Front Oncol. 2022 ;12 1042349
    Editorial: Women in cancer metabolism: 2021/2022.
    Tuuli Kaambre.
      
    Keywords:  cancer; cancer models in vivo; mechanisms; metabolism; metabolites; metastasis
    DOI:  https://doi.org/10.3389/fonc.2022.1042349
  9. Cancers (Basel). 2022 Dec 18. pii: 6240. [Epub ahead of print]14(24):
    Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML.
    Debbie C Strachan, Christine J Gu, Ryosuke Kita, Erica K Anderson, Michelle A Richardson, George Yam, Graham Pimm, Jordan Roselli, Alyssa Schweickert, Maci Terrell, Raushan Rashid, Alan K Gonzalez, Hailey H Oviedo, Michelle C Alozie, Tamilini Ilangovan, Andrea N Marcogliese, Hiroomi Tada, Marianne T Santaguida, Alexandra M Stevens.
      Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in leukemic blasts relative to the control. In pediatric patients treated with conventional chemotherapy, comprising cytarabine, daunorubicin and etoposide (ADE), ex vivo drug sensitivity results correlated with minimal residual disease (r = 0.63) and one year relapse-free survival (r = 0.70; AUROC = 0.94). In the de novo ADE analysis cohort of 13 patients, AML cells showed greater sensitivity to bortezomib/panobinostat compared with ADE, and comparable sensitivity between venetoclax/azacitidine and ADE ex vivo. Two patients showed a differential response between ADE and bortezomib/panobinostat, thus supporting the incorporation of ex vivo drug sensitivity testing in clinical trials to further evaluate the predictive utility of this platform in children with AML.
    Keywords:  ADE; bortezomib; combination therapy; ex vivo drug sensitivity; flow cytometry; panobinostat; pediatric acute myeloid leukemia; personalized medicine; precision medicine
    DOI:  https://doi.org/10.3390/cancers14246240
  10. Cells. 2022 Dec 18. pii: 4113. [Epub ahead of print]11(24):
    Mitochondria Drive Immune Responses in Critical Disease.
    Shilpa Tiwari-Heckler, Simon C Robson, Maria Serena Longhi.
      Mitochondria engage in multiple cellular and extracellular signaling pathways ranging from metabolic control, antiviral and antibacterial host defense to the modulation of inflammatory responses following cellular damage and stress. The remarkable contributions of these organelles to innate and adaptive immunity, shape cell phenotype and modulate their functions during infection, after trauma and in the setting of inflammatory disease. We review the latest knowledge of mitochondrial biology and then discuss how these organelles may impact immune cells to drive aberrant immune responses in critical disease.
    Keywords:  adaptive immunity; critical illness; immunometabolism; immunosuppression; inflammation; innate immunity; mitochondria; mitochondrial danger-associated-molecular-pattern; trauma
    DOI:  https://doi.org/10.3390/cells11244113
  11. BMC Cancer. 2022 Dec 21. 22(1): 1339
    Evaluating the prognostic value of CD56 in pediatric acute myeloid leukemia.
    Tianqi Liang, Zhiyong Peng, Chunfu Li, Junbin Huang, Huabin Wang, Chaoke Bu, Jian Li, Yongzhi Zheng, Xiaoqin Feng, Huiping Li, Chun Chen.
       BACKGROUND: Many cytogenetic changes and gene mutations are associated with acute myeloid leukemia (AML) survival outcomes. CD56 is related to poor prognosis when expressed in adult AML patients. However, the prognostic value of CD56 in children with AML has rarely been reported. In this research, we aimed to evaluate the prognostic value of CD56 in childhood AML.
    METHODS: The present retrospective study included 145 newly diagnosed pediatric patients with de novo AML (excluding AML-M3) in two hospitals between January 2015 and April 2021.
    RESULTS: The total median (range) age was 75 (8-176) months, and the median follow-up time was 35 months. No significant difference in the 3-year overall survival rate was noted between the CD56-positive and CD56-negative groups (67.0% vs. 79.3%, P = 0.157) who received chemotherapy. However, among high-risk patients, the CD56-positive group had a worse overall survival rate and event-free survival rate (P < 0.05). Furthermore, among high-risk patients, the CD56-positive group had higher relapse and mortality rates than the CD56-negative group (P < 0.05).
    CONCLUSIONS: CD56 represents a potential factor of poor prognosis in specific groups of children with AML and should be considered in the risk stratification of the disease. Given the independent prognostic value of CD56 expression, we should consider integrating this marker with some immunophenotypic or cytogenetic abnormalities for comprehensive analysis.
    Keywords:  Acute myeloid leukemia; CD56; Cytogenetic abnormality; Immunophenotype; Prognostic value; Risk stratification
    DOI:  https://doi.org/10.1186/s12885-022-10460-3
  12. Science. 2022 Dec 23. 378(6626): 1267
    Moms' mitochondria may refresh cells in sick kids.
    Mitch Leslie.
      Technique is designed to treat mitochondrial disease.
    DOI:  https://doi.org/10.1126/science.adg3936
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