bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–04–09
sixteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.
  2. The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia.
  3. OXPHOS inhibitors, metabolism and targeted therapies in cancer.
  4. Targeting glutamine metabolism as a therapeutic strategy for cancer.
  5. MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
  6. Overcoming anti-PD-1/PD-L1 immune checkpoint blockade resistance: the role of macrophage, neutrophils and mast cells in the tumor microenvironment.
  7. Epigenomic machinery regulating pediatric AML: clonal expansion mechanisms, therapies, and future perspectives.
  8. Short-course Venetoclax With Standard Chemotherapy Is Effective in Early T-cell Precursor Acute Lymphoblastic Leukemia.
  9. Simultaneous inhibition of PD-1 and LAG-3: the future of immunotherapy?
  10. Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.
  11. Cancer stem cell-derived exosome-induced metastatic cancer: An orchestra within the tumor microenvironment.
  12. Mitochondria in Health, Disease, and Ageing.
  13. Tumor microenvironment signaling and therapeutics in cancer progression.
  14. The relationship between autophagy and PD-L1 and their role in antitumor therapy.
  15. Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
  16. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia.
  1. Haematologica. 2023 Apr 06.
    Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.
    Cristiana O'Brien, Tianyi Ling, Jacob M Berman, Rachel Culp-Hill, Julie A Reisz, Vincent Rondeau, Soheil Jahangiri, Jonathan St-Germain, Vinitha Macwan, Audrey Astori, Andy Zeng, Jun Young Hong, Meng Li, Min Yang, Sadhan Jana, Fabia Gamboni, Emily Tsao, Weiyi Liu, John E Dick, Hening Lin, Ari Melnick, Anastasia Tikhonova, Andrea Arruda, Mark D Minden, Brian Raught, Angelo D'Alessandro, Courtney L Jones.
      Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease initiating leukemia stem cells (LSCs). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSCs. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSCs. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSCs but is not essential for normal human hematopoietic stem and progenitor cell (HSPC) function. To elucidate the molecular mechanisms by which SIRT3 is essential in LSCs we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support oxidative phosphorylation and ATP production in human LSCs. Further, we discovered two approaches to further sensitize LSCs to SIRT3 inhibition. First, we found that LSCs tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSCs to YC8-02 and potentiates LSC cell death. Second, SIRT3 inhibition sensitizes LSCs to BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.
    DOI:  https://doi.org/10.3324/haematol.2022.281894
  2. Biochem Pharmacol. 2023 Apr 04. pii: S0006-2952(23)00130-2. [Epub ahead of print] 115539
    The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia.
    Qian Li, Mengyuan Wang, Lingbo Liu.
      Acute myeloid leukemia (AML) is an aggressive malignancy of myeloid hematopoietic cells, which is characterized by the aberrant clonal proliferation of immature myeloblasts and compromised hematopoiesis. The leukemic cell population is strongly heterogeneous. Leukemic stem cells (LSCs) are an important leukemic cell subset with stemness characteristics and self-renewal ability, which contribute to the development of refractory or relapsed AML. It is now acknowledged that LSCs develop from hematopoietic stem cells (HSCs) or phenotypically directed cell populations with transcriptional stemness characteristics under selective pressure from the bone marrow (BM) niche. Exosomes are extracellular vesicles containing bioactive substances involved in intercellular communication and material exchange under steady state and pathological conditions. Several studies have reported that exosomes mediate molecular crosstalk between LSCs, leukemic blasts, and stromal cells in the BM niche, promoting LSC maintenance and AML progression. This review briefly describes the process of LSC transformation and the biogenesis of exosomes, highlighting the role of leukemic-cell- and BM-niche-derived exosomes in the maintenance of LSCs and AML progression. In addition, we discuss the potential application of exosomes in the clinic as biomarkers, therapeutic targets, and carriers for targeted drug delivery.
    Keywords:  Acute myeloid leukemia; Bone marrow niche; Drug resistance; Exosomes; Leukemic stem cells; Stemness maintenance
    DOI:  https://doi.org/10.1016/j.bcp.2023.115539
  3. Biochem Pharmacol. 2023 Apr 03. pii: S0006-2952(23)00122-3. [Epub ahead of print]211 115531
    OXPHOS inhibitors, metabolism and targeted therapies in cancer.
    Octavia Cadassou, Lars Petter Jordheim.
      More and more studies highlight the complex metabolic characteristics and plasticity of cancer cells. To address these specificities and explore the associated vulnerabilities, new metabolism-targeting therapeutic strategies are being developed. It is more and more accepted that cancer cells do not produce their energy only from aerobic glycolysis, as some subtypes strongly rely on mitochondrial respiration (OXPHOS). This review focuses on classical and promising OXPHOS inhibitors (OXPHOSi), unravelling their interest and modes of actions in cancer, particularly in combination with other strategies. Indeed, in monotherapy, OXPHOSi display limited efficiency as they mostly trigger cell death in cancer cell subtypes that strongly depend on mitochondrial respiration and are not able to shift to other metabolic pathways to produce energy. Nevertheless, they remain very interesting in combination with conventional therapeutic strategies such as chemotherapy and radiotherapy, increasing their anti-tumoral actions. In addition, OXPHOSi can be included in even more innovative strategies such as combinations with other metabolic drugs or immunotherapies.
    Keywords:  Cancer metabolism; Drug combination; Immunotherapy; Metabolic plasticity; Mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.bcp.2023.115531
  4. Exp Mol Med. 2023 Apr 03.
    Targeting glutamine metabolism as a therapeutic strategy for cancer.
    Jonghwa Jin, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.
      Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis. To date, many studies have explored the role of glutamine metabolism in cancer, thereby providing a scientific rationale for targeting glutamine metabolism for cancer treatment. In this review, we summarize the mechanism(s) involved at each step of glutamine metabolism, from glutamine transporters to redox homeostasis, and highlight areas that can be exploited for clinical cancer treatment. Furthermore, we discuss the mechanisms underlying cancer cell resistance to agents that target glutamine metabolism, as well as strategies for overcoming these mechanisms. Finally, we discuss the effects of glutamine blockade on the tumor microenvironment and explore strategies to maximize the utility of glutamine blockers as a cancer treatment.
    DOI:  https://doi.org/10.1038/s12276-023-00971-9
  5. Autophagy Rep. 2022 ;1(1): 210-213
    MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
    Priyanka Gajwani, Jalees Rehman.
      Differentiating stem cells must adapt their mitochondrial metabolism to fit the needs of the mature differentiated cell. In a recent study, we observed that during differentiation to an endothelial phenotype, pluripotent stem cell mitochondria are removed by mitophagy, triggering compensatory mitochondrial biogenesis to replenish the mitochondrial pool. We identified the mitochondrial phosphatase PGAM5 as the link between mitophagy and transcription of the mitochondrial biogenesis regulator PPARGC1A/PGC1α in the nucleus. Swapping of mitochondria through the coupled processes of mitophagy and mitochondrial biogenesis lead to enhanced metabolic reprogramming in the differentiated cell.
    Keywords:  CTNNB1/β-catenin; PINK1; PPARGC1A/PGC1α; differentiation; endothelium; mitochondrial biogenesis; mitofusin 2; mitophagy; stem cells
    DOI:  https://doi.org/10.1080/27694127.2022.2071549
  6. Clin Exp Med. 2023 Apr 06.
    Overcoming anti-PD-1/PD-L1 immune checkpoint blockade resistance: the role of macrophage, neutrophils and mast cells in the tumor microenvironment.
    Louis Boafo Kwantwi.
      In recent years, the anti-PD-1/PD-L1 blockade has become a game changer in cancer treatment following the unprecedented response rate. Regardless of the substantial therapy efficacy across various cancer types, some patients do not still respond to these therapies, indicating that a deeper understanding of the mechanisms of anti-PD-1/PD-L1 resistance is highly important. To overcome such resistance, the tumor-induced immunosuppressive mechanisms have been focused and several suppressor cell populations in the tumor microenvironment have been identified. Among these cells, macrophages, neutrophils, and mast cells are known to play key roles in anti-PD-1/PD-L1 resistance. Hence, gaining control over these innate immune cells can open opportunities for breaking tumor resistance to immune checkpoint inhibitors. Herein, a summary of the role of macrophages, neutrophils, and mast cells in anti-PD-1/PD-L1 resistance has been described. Also, strategies to overcome their therapeutic resistance to anti-PD-1/PD-L1 have been discussed.
    Keywords:  Anti-PD-L1/PD-1; Immune checkpoint blockade; Tumor-associated macrophages; Tumor-associated mast cells; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1007/s10238-023-01059-4
  7. Semin Cancer Biol. 2023 Mar 30. pii: S1044-579X(23)00050-0. [Epub ahead of print]
    Epigenomic machinery regulating pediatric AML: clonal expansion mechanisms, therapies, and future perspectives.
    Ugo Chianese, Chiara Papulino, Wout Megchelenbrink, Francesco Paolo Tambaro, Fortunato Ciardiello, Rosaria Benedetti, Lucia Altucci.
      Acute myeloid leukemia (AML) is a heterogeneous disease with a genetic, epigenetic, and transcriptional etiology mainly presenting somatic and germline abnormalities. AML incidence rises with age but can also occur during childhood. Pediatric AML (pAML) accounts for 15-20% of all pediatric leukemias and differs considerably from adult AML. Next-generation sequencing technologies have enabled the research community to "paint" the genomic and epigenomic landscape in order to identify pathology-associated mutations and other prognostic biomarkers in pAML. Although current treatments have improved the prognosis for pAML, chemoresistance, recurrence, and refractory disease remain major challenges. In particular, pAML relapse is commonly caused by leukemia stem cells that resist therapy. Marked patient-to-patient heterogeneity is likely the primary reason why the same treatment is successful for some patients but, at best, only partially effective for others. Accumulating evidence indicates that patient-specific clonal composition impinges significantly on cellular processes, such as gene regulation and metabolism. Although our understanding of metabolism in pAML is still in its infancy, greater insights into these processes and their (epigenetic) modulation may pave the way toward novel treatment options. In this review, we summarize current knowledge on the function of genetic and epigenetic (mis)regulation in pAML, including metabolic features observed in the disease. Specifically, we describe how (epi)genetic machinery can affect chromatin status during hematopoiesis, leading to an altered metabolic profile, and focus on the potential value of targeting epigenetic abnormalities in precision and combination therapy for pAML. We also discuss the possibility of using alternative epidrug-based therapeutic approaches that are already in clinical practice, either alone as adjuvant treatments and/or in combination with other drugs.
    Keywords:  epigenetic drugs; epigenetics; metabolism; pAML
    DOI:  https://doi.org/10.1016/j.semcancer.2023.03.009
  8. J Pediatr Hematol Oncol. 2023 Apr 04.
    Short-course Venetoclax With Standard Chemotherapy Is Effective in Early T-cell Precursor Acute Lymphoblastic Leukemia.
    Pronamee Borah, Nitin Dayal, Sangeeta Pathak, Rahul Naithani.
       BACKGROUND: Early T-cell precursor acute lymphoblastic leukemia (ETP ALL) is a high-risk subgroup of acute lymphoblastic leukemia characterized by unique immune phenotype and disease biology. ETP ALL cells share similarities with hematopoietic stem cells and myeloid progenitor cells. These patients have lower rates of complete remission and overall survival. High BCL2 expression is the main rationale for using venetoclax in ETP ALL.
    RESULTS: We report the treatment outcomes of 2 patients with ETP ALL who achieved minimal residual disease negative remission with the short course of venetoclax.
    CONCLUSIONS: Combination therapy of short-course venetoclax with Berlin-Frankfurt-Meunster 95 regimen is an effective regimen for treating patients with ETP ALL.
    DOI:  https://doi.org/10.1097/MPH.0000000000002672
  9. Immunotherapy. 2023 Apr 03.
    Simultaneous inhibition of PD-1 and LAG-3: the future of immunotherapy?
    Sasha-Jane Abi-Aad, Joseph Zouein, Antoine Chartouni, Nabih Naim, Hampig Raphael Kourie.
      Immunotherapy has improved the prognosis of many cancers, yet a large number of patients have demonstrated resistance to current immune checkpoint inhibitors. LAG-3 is an immune checkpoint expressed on tumor-infiltrating lymphocytes CD4+ and CD8+, Tregs and other immune cells. Coexpression of PD-1 and LAG-3 in solid or hematological cancers is generally associated with a poor prognosis and may be responsible for immunotherapy resistance. Dual inhibition therapy in the RELATIVITY-047 trial significantly improved progression-free survival in metastatic melanoma. This article discusses the presence of a possible synergistic interaction between LAG-3 and PD-1 in the tumor microenvironment and the utility of targeting both immune checkpoint inhibitors as an effective way to bypass resistance and increase treatment efficacy.
    Keywords:  LAG-3; anti-LAG-3; immune checkpoint inhibitors; relatlimab
    DOI:  https://doi.org/10.2217/imt-2022-0185
  10. Genes Dis. 2023 Jan;10(1): 7-9
    Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.
    Nian Jiang, Bowen Xie, Ming Fan, Jian Jian Li.
      Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.
    Keywords:  CD47; Immune checkpoint; Immunotherapy; Metabolic rewiring; Radiation therapy; Tumor acquired resistance
    DOI:  https://doi.org/10.1016/j.gendis.2022.07.019
  11. Biochimie. 2023 Apr 01. pii: S0300-9084(23)00076-7. [Epub ahead of print]
    Cancer stem cell-derived exosome-induced metastatic cancer: An orchestra within the tumor microenvironment.
    Khalid Rashid, Aqeel Ahmad, Semmal Syed Meerasa, Abdul Q Khan, Xiaobo Wu, Li Liang, Yuehong Cui, Tianshu Liu.
      Although the mechanisms as well as pathways associated with cancer stem cell (CSC) maintenance, expansion, and tumorigenicity have been extensively studied and the role of tumor cell (TC)-derived exosomes in this process is well understood, there is a paucity of research focusing specifically on the functional mechanisms of CSC-derived exosomes (CSC-Exo)/exosomal-ncRNAs and their impact on malignancy. This shortcoming needs to be addressed, given that these vesicular and molecular components of CSCs could have a great impact on the cancer initiation, progression, and recurrence through their interaction with other key tumor microenvironment (TME) components, such as MSCs/MSC-Exo and CAFs/CAF-Exo. In particular, understanding CSCs/CSC-Exo and its crosstalk with MSCs/MSC-Exo or CAFs/CAF-Exo that are associated with the proliferation, migration, differentiation, angiogenesis, and metastasis through an enhanced process of self-renewal, chemotherapy as well as radiotherapy resistance may aid cancer treatment. This review contributes to this endeavor by summarizing the characteristic features and functional mechanisms of CSC-Exo/MSC-Exo/CAF-Exo and their mutual impact on cancer progression and therapy resistance.
    Keywords:  CSC-Exos; CSC-Markers; Cancer stem cells; Chemoresistance; EMT; Metastasis; ncRNAs
    DOI:  https://doi.org/10.1016/j.biochi.2023.03.014
  12. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  13. Cancer Commun (Lond). 2023 Apr 02.
    Tumor microenvironment signaling and therapeutics in cancer progression.
    Anshika Goenka, Fatima Khan, Bhupender Verma, Priyanka Sinha, Crismita C Dmello, Manasi P Jogalekar, Prakash Gangadaran, Byeong-Cheol Ahn.
      Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.
    Keywords:  3D-model; cancer therapy; gut microbiota; immune signaling; metabolism; signaling; tumor microenvironment
    DOI:  https://doi.org/10.1002/cac2.12416
  14. Front Immunol. 2023 ;14 1093558
    The relationship between autophagy and PD-L1 and their role in antitumor therapy.
    Yu Cui, Jinfeng Shi, Youbin Cui, Zhanpeng Zhu, Wei Zhu.
      Immune checkpoint blockade therapy is an important advance in cancer treatment, and the representative drugs (PD-1/PD-L1 antibodies) have greatly improved clinical outcomes in various human cancers. However, since many patients still experience primary resistance, they do not respond to anti-PD1/PD-L1 therapy, and some responders also develop acquired resistance after an initial response. Therefore, combined therapy with anti-PD-1/PD-L1 immunotherapy may result in better efficacy than monotherapy. In tumorigenesis and tumor development processes, the mutual regulation of autophagy and tumor immune escape is an intrinsic factor of malignant tumor progression. Understanding the correlation between the tumor autophagy pathway and tumor immune escape may help identify new clinical cancer treatment strategies. Since both autophagy and immune escape of tumor cells occur in a relatively complex microenvironmental network, autophagy affects the immune-mediated killing of tumor cells and immune escape. Therefore, comprehensive treatment targeting autophagy and immune escape to achieve "immune normalization" may be an important direction for future research and development. The PD-1/PD-L1 pathway is essential in tumor immunotherapy. High expression of PD-L1 in different tumors is closely related to poor survival rates, prognoses, and treatment effects. Therefore, exploring the mechanism of PD-L1 expression is crucial to improve the efficacy of tumor immunotherapy. Here, we summarize the mechanism and mutual relationship between autophagy and PD-L1 in antitumor therapy, which may help enhance current antitumor immunotherapy approaches.
    Keywords:  PD-1; PD-L1; antitumor therapy; autophagy; tumor escape
    DOI:  https://doi.org/10.3389/fimmu.2023.1093558
  15. Nat Cell Biol. 2023 Apr 03.
    Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
    Jordan A Berg, Youjia Zhou, Yeyun Ouyang, Ahmad A Cluntun, T Cameron Waller, Megan E Conway, Sara M Nowinski, Tyler Van Ry, Ian George, James E Cox, Bei Wang, Jared Rutter.
      Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.
    DOI:  https://doi.org/10.1038/s41556-023-01117-9
  16. Open Med (Wars). 2023 ;18(1): 20220602
    TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia.
    Wei Zhang, Bei Liu, Shiwen Wu, Li Zhao.
      Acute myeloid leukemia (AML) is classified into favorable-risk, intermediate-risk, and poor-risk subtypes. This study aimed to compare the serum proteomic signatures of the three AML subtypes and identify prognostic biomarkers for AML. Serum samples from patients with favorable-risk (n = 14), intermediate-risk (n = 19), and poor-risk AMLs (n = 18) were used for the analysis of tandem mass tag (TMT) labeling-based quantitative proteomics. Comparative analysis was performed to identify differentially expressed proteins (DEPs) between groups. Prognostic proteins were screened using binary logistics regression analysis. TMT-MS/MS proteomics analysis identified 138 DEPs. Fumarate hydratase (FH), isocitrate dehydrogenase 2 (IDH2), and enolase 1 (ENO1) were significantly upregulated in poor-risk patients compared with favorable-risk patients. ELISA assay confirmed that patients with poor-risk AMLs had higher levels of IDH2, ENO1, and FH compared with intermediate-risk AML patients. Logistics analysis identified that proteins 3-hydroxyacyl-CoA dehydrogenase type-2 (HADH, odds ratio (OR) = 1.035, p = 0.010), glutamine synthetase (GLUL, OR = 1.022, p = 0.039), and lactotransferrin (LTF, OR = 1.1224, p = 0.016) were associated with poor prognosis, and proteins ENO1 (OR = 1.154, p = 0.053), FH (OR = 1.043, p = 0.059), and IDH2 (OR = 3.350, p = 0.055) were associated with AML prognosis. This study showed that AML patients had elevated levels of FH, IDH2, ENO1, LTF, and GLUL proteins and might be at high risk of poor prognosis.
    Keywords:  TMT labeling-based quantitative proteomics; favorable-risk acute myeloid leukemia; isocitrate dehydrogenase 2; prognostic biomarker; proteomic profiling
    DOI:  https://doi.org/10.1515/med-2022-0602
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