bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–10–02
fiveteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting.
  2. AML-230 Predictive Value of CD34-Positive versus CD34-Negative Leukemic Stem Cells on Survival Outcome in Acute Myeloid Leukemia.
  3. Editorial: Acute myeloid leukemia (AML): Is it time for MRD-driven treatment?
  4. AML-250 Mitochondrial Respiration Regulates GPX4 Inhibition-Induced Ferroptosis in Acute Myeloid Leukemia.
  5. Metabolic determinants of stemness in medulloblastoma.
  6. The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies.
  7. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.
  8. Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification.
  9. AML-266 Optimization of a Drug Screening Platform in Acute Myeloid Leukemia.
  10. Loss of TET2 with reduced genomic 5-hmC is associated with adverse-risk AML.
  11. Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend?
  12. Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2-dependent glutaminolysis pathway.
  13. CD93 promotes acute myeloid leukemia development and is a potential therapeutic target.
  14. PGC-1β maintains mitochondrial metabolism and restrains inflammatory gene expression.
  15. Upregulation of PD-L1 in Senescence and Aging.
  1. Cell Death Discov. 2022 Sep 26. 8(1): 397
    The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting.
    Yongfeng Chen, Jing Li, Linglong Xu, Mihnea-Alexandru Găman, Zhenyou Zou.
      Acute myeloid leukemia (AML) is a hematological malignancy characterized by cytogenetic and genomic alterations. Up to now, combination chemotherapy remains the standard treatment for leukemia. However, many individuals diagnosed with AML develop chemotherapeutic resistance and relapse. Recently, it has been pointed out that leukemic stem cells (LSCs) are the fundamental cause of drug resistance and AML relapse. LSCs only account for a small subpopulation of all leukemic cells, but possess stem cell properties, including a self-renewal capacity and a multi-directional differentiation potential. LSCs reside in a mostly quiescent state and are insensitive to chemotherapeutic agents. When LSCs reside in a bone marrow microenvironment (BMM) favorable to their survival, they engage into a steady, continuous clonal evolution to better adapt to the action of chemotherapy. Most chemotherapeutic drugs can only eliminate LSC-derived clones, reducing the number of leukemic cells in the BM to a normal range in order to achieve complete remission (CR). LSCs hidden in the BM niche can hardly be targeted or eradicated, leading to drug resistance and AML relapse. Understanding the relationship between LSCs, the BMM, and the generation and evolution laws of LSCs can facilitate the development of effective therapeutic targets and increase the efficiency of LSCs elimination in AML.
    DOI:  https://doi.org/10.1038/s41420-022-01193-0
  2. Clin Lymphoma Myeloma Leuk. 2022 Oct;pii: S2152-2650(22)01248-4. [Epub ahead of print]22 Suppl 2 S226-S227
    AML-230 Predictive Value of CD34-Positive versus CD34-Negative Leukemic Stem Cells on Survival Outcome in Acute Myeloid Leukemia.
    Nupur Das, Devasis Panda, Ritu Gupta, Smeeta Gajendra, Sameer Bakhshi, Atul Sharma, Ranjit K Sahoo, Lalit Kumar, Sandeep Rai, Vijay K Prajapati, Saroj Singh.
       CONTEXT: Leukemic stem cells (LSCs) have emerged as a potential factor contributing to an overall dismal outcome in acute myeloid leukemia (AML).
    OBJECTIVE: In this study, using flowcytometric immunophenotyping (FCMI), we have demonstrated LSC identification and quantification in both the CD34+ and CD34-compartments to find its relevance in predicting treatment outcomes. Furthermore, we correlated the impact of LSC quantification at diagnosis as a predictor of long-term survival.
    DESIGN: This is a prospective analysis of patients diagnosed with AML (per standard WHO criteria).
    SETTING: Tertiary care cancer center.
    PATIENTS: A total of 161 patients with a diagnosis of non-acute promyelocytic leukemia (non-APL) AML patients diagnosed over a period of two years (January 2019 to December 2020) were evaluated.
    INTERVENTIONS: Bone marrow aspirates collected in EDTA were processed for FCMI using a stain-lyse-wash technique with a singletube, 10-color comprehensive antibody panel. LSCs were identified primarily in the CD34+CD38- compartment; however, in a substantial number of CD34- AML, LSCs were segregated from the CD34-CD38- compartment using CD117 as an alternate gating marker and CD123, CD33, and CD11b as LSC-specific markers in all cases.
    MAIN OUTCOME MEASURES: 1. CD34+ versus CD34-LSC and 2. Baseline LSC% as a predictor of survival.
    RESULTS: LSCs were identified in 82.6% (133/161) of patients. CD34+ LSCs and CD34- LSCs were isolated in 82.53% (104/126) and 82.85% (29/35) of cases, respectively. The median survival times (in weeks) in CD34- LSCs was higher than in CD34+ LSCs; EFS (54 vs. 47; P=0.27), RFS (79 vs. 48; P=0.14), and OS (121 vs. 71; P=0.41) were found to be comparable in both groups. Furthermore, the total study cohort was divided into three groups based on diagnostic LSC percentage, i.e., LSCneg (LSC% <0.004%), LSClow (LSC%=0.004%-0.892%), and LSChigh (LSC% >0.892%). The LSChigh group had significantly shorter OS, EFS, and RFS compared to the LSClow and LSCneg groups.
    CONCLUSIONS: This study confirms the presence of LSCs beyond the usual CD34+CD38- compartment; however, there is no difference in survival outcomes in both groups. Also, LSC quantification is a powerful and independent prognostic parameter in AML predicting long-term survival and risk of relapse.
    Keywords:  AML; flow cytometry; leukemic stem cells; survival outcome
    DOI:  https://doi.org/10.1016/S2152-2650(22)01248-4
  3. Front Oncol. 2022 ;12 1020185
    Editorial: Acute myeloid leukemia (AML): Is it time for MRD-driven treatment?
    Fabio Guolo, Claudio Cerchione, Chiara Vernarecci, Alessandro Isidori.
      
    Keywords:  acute myeloid leukemia (AML); allogeneic stem cell transplantation; immunotherapy; leukemic stem cell (LSC); minimal residual disease (MRD)
    DOI:  https://doi.org/10.3389/fonc.2022.1020185
  4. Clin Lymphoma Myeloma Leuk. 2022 Oct;pii: S2152-2650(22)01253-8. [Epub ahead of print]22 Suppl 2 S229
    AML-250 Mitochondrial Respiration Regulates GPX4 Inhibition-Induced Ferroptosis in Acute Myeloid Leukemia.
    Hiroki Akiyama, Ran Zhao, Yuki Nishida, Lauren Ostermann, Poo Yee Mak, Edward Ayoub, Sujan Piya, Bing Carter, Michael Andreeff, Jo Ishizawa.
       CONTEXT: Ferroptosis, a form of non-apoptotic cell death regulated by iron-dependent lipid peroxidation, has drawn extensive attention as a potential anti-cancer strategy. However, it remains to be explored in hematologic malignancies. We here investigate the molecular mechanisms of ferroptosis in acute myeloid leukemia (AML) and its therapeutic potential of co-targeting mitochondrial respiration.
    RESULTS: Analyses of publicly available databases (TCGA, DepMap) showed that AML patients with higher mRNA expression of major anti-ferroptotic genes had significantly shorter survival and that leukemia cells are one of the cell types that are highly dependent on GPX4 among other cancers. This suggests the potential prognostic impact and relevance in therapeutics of this pathway in AML. Indeed, pharmacological inhibition or genetic knockdown of a well-established anti-ferroptosis regulator GPX4 induced profound ferroptosis, evidenced by dependency on iron and lipid peroxidation. Importantly, the induced cell death was agonistic of TP53 mutational status. As a potentially AML-specific mechanism that is unusual in solid tumor models, we found that GPX4 inhibition-induced ferroptosis was efficiently blocked by the mitochondria-targeted ubiquinone MitoQ in AML cells. Ubiquinone is an endogenous antioxidant protecting cells from lipid peroxidation, and in the mitochondria, the respiratory chain is essential for the recycling of ubiquinone. Thus, we hypothesized that mitochondria protect AML cells from ferroptosis by activating the ubiquinone cycle. Consistently, mitochondrial DNA-depleted HL60 Rho0 cells, which lack mitochondrial respiration, were more sensitive to ML210 compared to the parental cells. To translate this finding to a pharmacological approach, we utilized the imipridone ONC201, which hyperactivates mitochondrial protease ClpP to degrade mitochondrial proteins, including the respiratory chain complex, and exerts cancer-selective lethality (Ishizawa et al. Cancer Cell 2019). Indeed, the combination of ONC201 and ML210 resulted in synergistic anti-leukemia effects in primary AML cells. The combinatorial effect was also validated by utilizing genetically engineered AML cells (genetic knockdown of GPX4 or overexpression of hyperactivated mutant ClpP).
    CONCLUSIONS: GPX4 inhibition induces ferroptosis involving mitochondrial redox machinery in AML. Combinatorial targeting of mitochondrial respiration with GPX4 inhibition exerts synergistic anti-leukemia effects. Further studies are in progress to assess the molecular mechanisms and the in-vivo efficacy of the combinatorial treatments.
    Keywords:  AML; ClpP; GPX4; ferroptosis; mitochondrial respiration
    DOI:  https://doi.org/10.1016/S2152-2650(22)01253-8
  5. World J Stem Cells. 2022 Aug 26. 14(8): 587-598
    Metabolic determinants of stemness in medulloblastoma.
    Paula Martín-Rubio, Pilar Espiau-Romera, Alba Royo-García, Laia Caja, Patricia Sancho.
      Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glut athione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.
    Keywords:  Cancer stem cells; Glycolysis; Lipids; Medulloblastoma; Metabolism; Stemness
    DOI:  https://doi.org/10.4252/wjsc.v14.i8.587
  6. Front Oncol. 2022 ;12 984560
    The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies.
    Danting Wang, Qizhen Ye, Haochen Gu, Zhigang Chen.
      Aberrant lipid metabolism is nonnegligible for tumor cells to adapt to the tumor microenvironment (TME). It plays a significant role in the amount and function of immune cells, including tumor-associated macrophages, T cells, dendritic cells and marrow-derived suppressor cells. It is well-known that the immune response in TME is suppressed and lipid metabolism is closely involved in this process. Immunotherapy, containing anti-PD1/PDL1 therapy and adoptive T cell therapy, is a crucial clinical cancer therapeutic strategy nowadays, but they display a low-sensibility in certain cancers. In this review, we mainly discussed the importance of lipid metabolism in the formation of immunosuppressive TME, and explored the effectiveness and sensitivity of immunotherapy treatment by regulating the lipid metabolism.
    Keywords:  immune cells; immunotherapy; lipid metabolism; microenvironment; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.984560
  7. Nature. 2022 Sep 28.
    PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.
    Masao Hashimoto, Koichi Araki, Maria A Cardenas, Peng Li, Rohit R Jadhav, Haydn T Kissick, William H Hudson, Donald J McGuire, Rebecca C Obeng, Andreas Wieland, Judong Lee, Daniel T McManus, James L Ross, Se Jin Im, Junghwa Lee, Jian-Xin Lin, Bin Hu, Erin E West, Christopher D Scharer, Gordon J Freeman, Arlene H Sharpe, Suresh S Ramalingam, Alex Pellerin, Volker Teichgräber, William J Greenleaf, Christian Klein, Jorg J Goronzy, Pablo Umaña, Warren J Leonard, Kendall A Smith, Rafi Ahmed.
      Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
    DOI:  https://doi.org/10.1038/s41586-022-05257-0
  8. Front Oncol. 2022 ;12 947492
    Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification.
    Yijing Zhao, Li-Ting Niu, Li-Juan Hu, Meng Lv.
       Background: Enoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34+ progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified.
    Methods: In the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People's Hospital and tested for ECHDC3 in enriched CD34+ cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature.
    Results: By Kaplan-Meier analysis, patients with ECHDC3high demonstrated inferior overall survival (OS) compared to those with ECHDC3low both in the training (2-year OS, 55.6% vs. 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% vs. 24.3%, p = 0.002). In addition, ECHDC3high predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% vs. 26.3%, p = 0.039) or FLT3+NPM1- adverse (adv) risk (4-year OS, 6.4% vs. 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013-1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% vs. 23.5%, p < 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin.
    Conclusion: These bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.
    Keywords:  ECHDC3; acute myeloid leukemia; chemoresistance; immune cell infiltration; re-stratification
    DOI:  https://doi.org/10.3389/fonc.2022.947492
  9. Clin Lymphoma Myeloma Leuk. 2022 Oct;pii: S2152-2650(22)01258-7. [Epub ahead of print]22 Suppl 2 S232
    AML-266 Optimization of a Drug Screening Platform in Acute Myeloid Leukemia.
    Laureen Chat, Justine Pasanisi, Kim Pacchiardi, Alya Pioton, Matthieu Duchmann, Raphaël Itzykson.
       CONTEXT: Acute myeloid leukemia (AML) is a group of hematological diseases with a poor prognosis. Functional ex-vivo drug screening of primary AML cells could identify patient-specific vulnerabilities and improve the treatment of AML patients. To determine the chemosensitivity of primary cells from AML patients, we previously developed a multiparametric niche-like drug screening platform (NEXT platform, Reinaldo Dal Bello, ASH, 2020).
    OBJECTIVE: Optimization of an ex-vivo niche-like drug screening platform on primary AML samples to prospectively recommend second-line treatment for AML patients.
    SETTINGS: Primary cells from 49 consecutive patients with newly diagnosed AML were cultured for 72 hours in niche-like conditions (conditioned media, mesenchymal stroma, hypoxia) and exposed to 36 molecules at 8 concentrations. Subsequently, total leukemic cells, blasts, lymphocytes, differentiated cells, and leukemic stem cell counts were assessed using multiparametric high-throughput flow cytometry (iQue3 Intellycyt). Drug activity was assessed using a drug sensitivity score (DSS, Yadov et al., Scientific Reports, 2014) after normalization to DMSO controls. A drug was considered inactive (DSS=0), moderately effective (0<DSS<50), or very effective (DSS≥50).
    RESULTS: We validated the use of frozen cells that provided a similar number of live cells (3492±2808, n=32) as fresh samples (2,398±2,567, n=5, P=0.29). We upscaled the assay to a 384-well plate to increase the number of tested drugs, with a minimum of 7.5 million cells required for testing the 36 drugs. Across the 49 patients, the median number of drugs with strong or moderate activity was 4 (range 0 to 13). In 42 (86%) patients, at least one drug had moderate activity and 22 (49%) had strong activity. We identified 6 top drugs that are moderately effective or very effective in more than 40% of patients: selinexor, ponatinib, palbociclib, sunitinib, and S63845.
    CONCLUSIONS: During this study, we validated and upscaled our NEXT platform on 49 patients. The prospective application of our niche-like drug screening platform is now being investigated in relapsed/refractory AML patients accrued to the multicenter study ALFA-PPP (NCT04777916).
    Keywords:  AML; acute myeloid leukemia; drug screening; precision medicine
    DOI:  https://doi.org/10.1016/S2152-2650(22)01258-7
  10. Leuk Lymphoma. 2022 Sep 27. 1-7
    Loss of TET2 with reduced genomic 5-hmC is associated with adverse-risk AML.
    Karthikeyan Pethusamy, Ashikh Seethy, Ruby Dhar, Abhibroto Karmakar, Shilpi Chaudhary, Sameer Bakhshi, Jayanth Kumar P, Anita Chopra, Shyam S Chauhan, Subhradip Karmakar.
      While considerable information exists on the ten-eleven translocation 2 (TET2) mutational landscape in AML, the information on TET2 expression is limiting. So, we aimed to study the TET2 expression at mRNA and protein levels in AML patients compared to healthy controls. To achieve this, we recruited 70 non-M3, de novo AML patients and 20 healthy controls. The expression of TET2 was checked at mRNA and protein levels by qPCR and ELISA respectively and the TET activity was checked by the 5-hmC assay. TET2 mRNA expression was correlated with clinicopathological parameters and overall survival. We found a significant downregulation of TET2 mRNA and protein and significantly lower DNA 5-hmC levels in AML patients compared to controls. TET2 downregulation was more in patients with high blast counts and patients of the adverse-risk ELN category. We also found a significant upregulation of DNMT1 and DNMT3a suggesting a hypermethylation phenotype in de novo AML.
    Keywords:  Acute myeloid leukemia; DNMT; TET2; cancer epigenetics
    DOI:  https://doi.org/10.1080/10428194.2022.2126278
  11. J Biomed Sci. 2022 Sep 26. 29(1): 74
    Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend?
    Cheng-Liang Kuo, Ananth Ponneri Babuharisankar, Ying-Chen Lin, Hui-Wen Lien, Yu Kang Lo, Han-Yu Chou, Vidhya Tangeda, Li-Chun Cheng, An Ning Cheng, Alan Yueh-Luen Lee.
      The major concept of "oxidative stress" is an excess elevated level of reactive oxygen species (ROS) which are generated from vigorous metabolism and consumption of oxygen. The precise harmonization of oxidative stresses between mitochondria and other organelles in the cell is absolutely vital to cell survival. Under oxidative stress, ROS produced from mitochondria and are the major mediator for tumorigenesis in different aspects, such as proliferation, migration/invasion, angiogenesis, inflammation, and immunoescape to allow cancer cells to adapt to the rigorous environment. Accordingly, the dynamic balance of oxidative stresses not only orchestrate complex cell signaling events in cancer cells but also affect other components in the tumor microenvironment (TME). Immune cells, such as M2 macrophages, dendritic cells, and T cells are the major components of the immunosuppressive TME from the ROS-induced inflammation. Based on this notion, numerous strategies to mitigate oxidative stresses in tumors have been tested for cancer prevention or therapies; however, these manipulations are devised from different sources and mechanisms without established effectiveness. Herein, we integrate current progress regarding the impact of mitochondrial ROS in the TME, not only in cancer cells but also in immune cells, and discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects.
    Keywords:  Cisplatin resistance; Combination cancer immunotherapy; Hypoxia; Immunoescape; Inflammation; Lon protease (LonP1); Mitochondrial chaperone; Mitochondrial reactive oxygen species (mtROS); Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12929-022-00859-2
  12. Sci Adv. 2022 Sep 30. 8(39): eabq0117
    Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2-dependent glutaminolysis pathway.
    Peng Wei, Alex J Bott, Ahmad A Cluntun, Jeffrey T Morgan, Corey N Cunningham, John C Schell, Yeyun Ouyang, Scott B Ficarro, Jarrod A Marto, Nika N Danial, Ralph J DeBerardinis, Jared Rutter.
      The fate of pyruvate is a defining feature in many cell types. One major fate is mitochondrial entry via the mitochondrial pyruvate carrier (MPC). We found that diffuse large B cell lymphomas (DLBCLs) consume mitochondrial pyruvate via glutamate-pyruvate transaminase 2 to enable α-ketoglutarate production as part of glutaminolysis. This led us to discover that glutamine exceeds pyruvate as a carbon source for the tricarboxylic acid cycle in DLBCLs. As a result, MPC inhibition led to decreased glutaminolysis in DLBCLs, opposite to previous observations in other cell types. We also found that MPC inhibition or genetic depletion decreased DLBCL proliferation in an extracellular matrix (ECM)-like environment and xenografts, but not in a suspension environment. Moreover, the metabolic profile of DLBCL cells in ECM is markedly different from cells in a suspension environment. Thus, we conclude that the synergistic consumption and assimilation of glutamine and pyruvate enables DLBCL proliferation in an extracellular environment-dependent manner.
    DOI:  https://doi.org/10.1126/sciadv.abq0117
  13. Exp Cell Res. 2022 Sep 22. pii: S0014-4827(22)00354-8. [Epub ahead of print]420(2): 113361
    CD93 promotes acute myeloid leukemia development and is a potential therapeutic target.
    Jie Jia, Bin Liu, Dandan Wang, Xiaohong Wang, Lingrui Song, Yanzhang Ren, Zhaoming Guo, Kun Ma, Changhao Cui.
      CD93 is a transmembrane receptor belonging to the Group XIV C-Type lectin family. It is expressed in a variety of cellular types such as monocytes, neutrophils, platelets, microglia, and endothelial cells. CD93 has been reported to play important roles in cell proliferation, cell migration, and tumor angiogenesis. Here, we show CD93 is highly expressed in M4 and M5 subtypes of acute myeloid leukemia (AML) patients, and highly expressed in leukemia stem cells, AML progenitor cells, as well as more differentiated AML cells. We found that CD93 promotes AML cell proliferation, while CD93 deficient AML cells commit to differentiation. We further show that CD93 exerts its proliferative function through downstream SHP-2/Syk/CREB cascade in AML cells. Moreover, human AML cells treated with CD93 mAb combined with αMFc-NC-DM1 (an IgG Fc specific antibody conjugated to maytansinoid DM1), showed a striking reduction of proliferation. Our study revealed that CD93 is a critical participator of AML development and provides a potential therapeutic cell surface target. (160 words).
    Keywords:  Acute myeloid leukemia; CD93; CD93 mAb; SHP-2/Syk/CREB cascade
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113361
  14. Sci Rep. 2022 Sep 26. 12(1): 16028
    PGC-1β maintains mitochondrial metabolism and restrains inflammatory gene expression.
    Hannah Guak, Ryan D Sheldon, Ian Beddows, Alexandra Vander Ark, Matthew J Weiland, Hui Shen, Russell G Jones, Julie St-Pierre, Eric H Ma, Connie M Krawczyk.
      Metabolic programming of the innate immune cells known as dendritic cells (DCs) changes in response to different stimuli, influencing their function. While the mechanisms behind increased glycolytic metabolism in response to inflammatory stimuli are well-studied, less is known about the programming of mitochondrial metabolism in DCs. We used lipopolysaccharide (LPS) and interferon-β (IFN-β), which differentially stimulate the use of glycolysis and oxidative phosphorylation (OXPHOS), respectively, to identify factors important for mitochondrial metabolism. We found that the expression of peroxisome proliferator-activated receptor gamma co-activator 1β (PGC-1β), a transcriptional co-activator and known regulator of mitochondrial metabolism, decreases when DCs are activated with LPS, when OXPHOS is diminished, but not with IFN-β, when OXPHOS is maintained. We examined the role of PGC-1β in bioenergetic metabolism of DCs and found that PGC-1β deficiency indeed impairs their mitochondrial respiration. PGC-1β-deficient DCs are more glycolytic compared to controls, likely to compensate for reduced OXPHOS. PGC-1β deficiency also causes decreased capacity for ATP production at steady state and in response to IFN-β treatment. Loss of PGC-1β in DCs leads to increased expression of genes in inflammatory pathways, and reduced expression of genes encoding proteins important for mitochondrial metabolism and function. Collectively, these results demonstrate that PGC-1β is a key regulator of mitochondrial metabolism and negative regulator of inflammatory gene expression in DCs.
    DOI:  https://doi.org/10.1038/s41598-022-20215-6
  15. Mol Cell Biol. 2022 Sep 26. e0017122
    Upregulation of PD-L1 in Senescence and Aging.
    Angelique Onorati, Aaron P Havas, Brian Lin, Jayaraj Rajagopal, Payel Sen, Peter D Adams, Zhixun Dou.
      Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis. However, senescent cells can also accumulate in aged and diseased tissues, contributing to inflammation and disease progression. The mechanisms mediating the impaired immune-mediated clearance of senescent cells are poorly understood. Here, we report that senescent cells upregulate the immune checkpoint molecule PD-L1, the ligand for PD-1 on immune cells, which drives immune cell inactivation. The induction of PD-L1 in senescence is dependent on the proinflammatory program. Furthermore, the secreted factors released by senescent cells are sufficient to upregulate PD-L1 in nonsenescent control cells, mediated by the JAK-STAT pathway. In addition, we show that prolongevity intervention rapamycin downregulates PD-L1 in senescent cells. Last, we found that PD-L1 is upregulated in several tissues in naturally aged mice and in the lungs of idiopathic pulmonary fibrosis patients. Together, our results report that senescence and aging are associated with upregulation of a major immune checkpoint molecule, PD-L1. Targeting PD-L1 may offer new therapeutic opportunities in treating senescence and age-associated diseases.
    Keywords:  PD-L1; SASP; aging; senescence
    DOI:  https://doi.org/10.1128/mcb.00171-22
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