bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023‒03‒12
thirteen papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Combinatorial BCL-2 family expression in Acute Myeloid Leukemia Stem Cells predicts clinical response to Azacitidine/Venetoclax.
  2. How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.
  3. Mitochondrial molecule controls inflammation.
  4. Editorial: Targeting cancer cell intracellular metabolism as a strategy against therapy resistance.
  5. Editorial: Cancer cell reprogramming: Impact on carcinogenesis and cancer progression.
  6. Disruption of mitochondrial oxidative phosphorylation by chidamide eradicates leukemic cells in AML.
  7. Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
  8. A Brief Review on Chemoresistance; Targeting Cancer Stem Cells as an Alternative Approach.
  9. Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.
  10. Targeting Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML): Moving beyond Prognostication.
  11. Targeting Mitochondrial Metabolic Reprogramming as a Potential Approach for Cancer Therapy.
  12. Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.
  13. The Question of Survival or Death: What Is the Role of Autophagy in Acute Myeloid Leukemia (AML)?
  1. Cancer Discov. 2023 Mar 09. pii: CD-22-0939. [Epub ahead of print]
    Combinatorial BCL-2 family expression in Acute Myeloid Leukemia Stem Cells predicts clinical response to Azacitidine/Venetoclax.
    Alexander Waclawiczek, Aino-Maija Leppa, Simon Renders, Karolin Stumpf, Cecilia Reyneri, Barbara Betz, Maike Janssen, Rabia Shahswar, Elisa Donato, Darja Karpova, Vera Thiel, Julia M Unglaub, Susanna Grabowski, Stefanie Gryzik, Lisa Vierbaum, Richard F Schlenk, Christoph Rollig, Michael Hundemer, Caroline Pabst, Michael Heuser, Simon Raffel, Carsten Muller-Tidow, Tim Sauer, Andreas Trumpp.
      The BCL-2 inhibitor Venetoclax (VEN) in combination with Azacitidine (5-AZA) is currently transforming Acute Myeloid Leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined therapy outcome. LSCs of 5-AZA/VEN refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators-of-Apoptosis-Combinatorial-Score" (MAC-Score) linking the ratio of protein expression of BCL-2, BCL-xL, and MCL-1 in LSCs. MAC-Scoring predicts initial response with a positive predictive-value of >97% associated to increased event-free survival. In summary, combinatorial levels of BCL-2-family members in AML-LSCs are a key denominator of response and MAC-Scoring reliably predicts patient response to 5-AZA/VEN.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0939
  2. Cancers (Basel). 2023 Feb 23. pii: 1417. [Epub ahead of print]15(5):
    How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.
    Zoé Daverio, Aneta Balcerczyk, Gilles J P Rautureau, Baptiste Panthu.
      Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research.
    Keywords:  Warburg effect; glucose deprivation; lactic acidosis; metabolic symbiosis; tumour heterogeneity
    DOI:  https://doi.org/10.3390/cancers15051417
  3. Nature. 2023 Mar 08.
    Mitochondrial molecule controls inflammation.
    Taylor A Poor, Navdeep S Chandel.
      
    Keywords:  Cell biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00596-y
  4. Front Oncol. 2023 ;13 1144821
    Editorial: Targeting cancer cell intracellular metabolism as a strategy against therapy resistance.
    Lingling Liu, Xiaohong Cai, Yuan Zhou, Chengsi He, Hongsheng Li, Xiangfu Liu, Zhengzhi Zou.
      
    Keywords:  cancer metabolism; cancer treatment; drug resistance; immune infiltration; tumor prognosis
    DOI:  https://doi.org/10.3389/fonc.2023.1144821
  5. Front Oncol. 2023 ;13 1152402
    Editorial: Cancer cell reprogramming: Impact on carcinogenesis and cancer progression.
    Yue Zhao, Simona Kranjc Brezar, Elvira V Grigorieva, Ira-Ida Skvortsova.
      
    Keywords:  cancer metabolism; cancer metastasis; cancer stem cell; carcinogenesis; cell reprogramming
    DOI:  https://doi.org/10.3389/fonc.2023.1152402
  6. Clin Transl Oncol. 2023 Mar 10.
    Disruption of mitochondrial oxidative phosphorylation by chidamide eradicates leukemic cells in AML.
    Jun-Dan Wang, Jue-Qiong Xu, Zi-Jie Long, Jian-Yu Weng.
      PURPOSE: Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting OXPHOS in AML is urgently needed.MATERIALS AND METHODS: Bioinformatical analysis of TCGA AML dataset was performed to identify the molecular signaling of OXPHOS. The OXPHOS level was measured through a Seahorse XFe96 cell metabolic analyzer. Flow cytometry was applied to measure mitochondrial status. Real-time qPCR and western blot were used to analyze the expression of mitochondrial or inflammatory factors. MLL-AF9-induced leukemic mice were conducted to measure the anti-leukemia effect of chidamide.
    RESULTS: Here, we reported that AML patients with high OXPHOS level were in a poor prognosis, which was associated with high expression of HDAC1/3 (TCGA). Inhibition of HDAC1/3 by chidamide inhibited cell proliferation and induced apoptotic cell death in AML cells. Intriguingly, chidamide could disrupt mitochondrial OXPHOS as assessed by inducing mitochondrial superoxide and reducing oxygen consumption rate, as well as decreasing mitochondrial ATP production. We also observed that chidamide augmented HK1 expression, while glycolysis inhibitor 2-DG could reduce the elevation of HK1 and improve the sensitivity of AML cells exposed to chidamide. Furthermore, HDAC3 was correlated with hyperinflammatory status, while chidamide could downregulate the inflammatory signaling in AML. Notably, chidamide eradicated leukemic cells in vivo and prolonged the survival time of MLL-AF9-induced AML mice.
    CONCLUSION: Chidamide disrupted mitochondrial OXPHOS, promoted cell apoptosis and reduced inflammation in AML cells. These findings exhibited a novel mechanism that targeting OXPHOS would be a novel strategy for AML treatment.
    Keywords:  Acute myeloid leukemia; Chidamide; HDAC; Mitochondria; OXPHOS
    DOI:  https://doi.org/10.1007/s12094-023-03079-8
  7. Elife. 2023 Mar 06. pii: e85494. [Epub ahead of print]12
    Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
    Chelsea U Kidwell, Joseph R Casalini, Soorya Pradeep, Sandra D Scherer, Daniel Greiner, Defne Bayik, Dionysios C Watson, Gregory S Olson, Justin D Lathia, Jarrod S Johnson, Jared Rutter, Alana L Welm, Thomas A Zangle, Minna Roh-Johnson.
      Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis1,2. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks3. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.
    Keywords:  cancer biology; cell biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.85494
  8. Int J Mol Sci. 2023 Feb 24. pii: 4487. [Epub ahead of print]24(5):
    A Brief Review on Chemoresistance; Targeting Cancer Stem Cells as an Alternative Approach.
    Belén Toledo, Aitor González-Titos, Pablo Hernández-Camarero, Macarena Perán.
      The acquisition of resistance to traditional chemotherapy and the chemoresistant metastatic relapse of minimal residual disease both play a key role in the treatment failure and poor prognosis of cancer. Understanding how cancer cells overcome chemotherapy-induced cell death is critical to improve patient survival rate. Here, we briefly describe the technical approach directed at obtaining chemoresistant cell lines and we will focus on the main defense mechanisms against common chemotherapy triggers by tumor cells. Such as, the alteration of drug influx/efflux, the enhancement of drug metabolic neutralization, the improvement of DNA-repair mechanisms, the inhibition of apoptosis-related cell death, and the role of p53 and reactive oxygen species (ROS) levels in chemoresistance. Furthermore, we will focus on cancer stem cells (CSCs), the cell population that subsists after chemotherapy, increasing drug resistance by different processes such as epithelial-mesenchymal transition (EMT), an enhanced DNA repair machinery, and the capacity to avoid apoptosis mediated by BCL2 family proteins, such as BCL-XL, and the flexibility of their metabolism. Finally, we will review the latest approaches aimed at decreasing CSCs. Nevertheless, the development of long-term therapies to manage and control CSCs populations within the tumors is still necessary.
    Keywords:  DNA repair; DNA-damaging drugs; cancer stem cells; chemoresistance; differentiation therapy; drug metabolism; drugs pumps; p53; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms24054487
  9. Nat Commun. 2023 Mar 08. 14(1): 1285
    Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.
    Matteo Maria Naldini, Gabriele Casirati, Matteo Barcella, Paola Maria Vittoria Rancoita, Andrea Cosentino, Carolina Caserta, Francesca Pavesi, Erika Zonari, Giacomo Desantis, Diego Gilioli, Matteo Giovanni Carrabba, Luca Vago, Massimo Bernardi, Raffaella Di Micco, Clelia Di Serio, Ivan Merelli, Monica Volpin, Eugenio Montini, Fabio Ciceri, Bernhard Gentner.
      Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts.
    DOI:  https://doi.org/10.1038/s41467-023-36969-0
  10. Int J Mol Sci. 2023 Mar 01. pii: 4790. [Epub ahead of print]24(5):
    Targeting Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML): Moving beyond Prognostication.
    Ing S Tiong, Sun Loo.
      Measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) has an established role in disease prognostication, particularly in guiding decisions for hematopoietic cell transplantation in first remission. Serial MRD assessment is now routinely recommended in the evaluation of treatment response and monitoring in AML by the European LeukemiaNet. The key question remains, however, if MRD in AML is clinically actionable or "does MRD merely portend fate"? With a series of new drug approvals since 2017, we now have more targeted and less toxic therapeutic options for the potential application of MRD-directed therapy. Recent approval of NPM1 MRD as a regulatory endpoint is also foreseen to drastically transform the clinical trial landscape such as biomarker-driven adaptive design. In this article, we will review (1) the emerging molecular MRD markers (such as non-DTA mutations, IDH1/2, and FLT3-ITD); (2) the impact of novel therapeutics on MRD endpoints; and (3) how MRD might be used as a predictive biomarker to guide therapy in AML beyond its prognostic role, which is the focus of two large collaborative trials: AMLM26 INTERCEPT (ACTRN12621000439842) and MyeloMATCH (NCT05564390).
    Keywords:  AML; MRD; NPM1; novel therapy; relapse
    DOI:  https://doi.org/10.3390/ijms24054790
  11. Int J Mol Sci. 2023 Mar 04. pii: 4954. [Epub ahead of print]24(5):
    Targeting Mitochondrial Metabolic Reprogramming as a Potential Approach for Cancer Therapy.
    Liufeng Zhang, Yuancheng Wei, Shengtao Yuan, Li Sun.
      Abnormal energy metabolism is a characteristic of tumor cells, and mitochondria are important components of tumor metabolic reprogramming. Mitochondria have gradually received the attention of scientists due to their important functions, such as providing chemical energy, producing substrates for tumor anabolism, controlling REDOX and calcium homeostasis, participating in the regulation of transcription, and controlling cell death. Based on the concept of reprogramming mitochondrial metabolism, a range of drugs have been developed to target the mitochondria. In this review, we discuss the current progress in mitochondrial metabolic reprogramming and summarized the corresponding treatment options. Finally, we propose mitochondrial inner membrane transporters as new and feasible therapeutic targets.
    Keywords:  cancer; drug development; metabolic reprogramming; mitochondria
    DOI:  https://doi.org/10.3390/ijms24054954
  12. Front Nutr. 2023 ;10 1113739
    Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.
    Zhangzuo Li, Qi Wang, Xufeng Huang, Mengting Yang, Shujing Zhou, Zhengrui Li, Zhengzou Fang, Yidan Tang, Qian Chen, Hanjin Hou, Li Li, Fei Fei, Qiaowei Wang, Yuqing Wu, Aihua Gong.
      Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which aerobic glycolysis, often known as the "Warburg effect," is essential to the fast proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant cells often remove lactate along with H+, yet the acidification of TME is inevitable. Not only does the highly concentrated lactate within the TME serve as a substrate to supply energy to the malignant cells, but it also works as a signal to activate multiple pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis, as well as immune escape. In this review, we aim to discuss the latest findings on lactate metabolism in tumor cells, particularly the capacity of extracellular lactate to influence cells in the tumor microenvironment. In addition, we examine current treatment techniques employing existing medications that target and interfere with lactate generation and transport in cancer therapy. New research shows that targeting lactate metabolism, lactate-regulated cells, and lactate action pathways are viable cancer therapy strategies.
    Keywords:  immune cells; immunity; lactate; metabolic; tumor microenvironment
    DOI:  https://doi.org/10.3389/fnut.2023.1113739
  13. Int J Hematol Oncol Stem Cell Res. 2022 Oct 01. 16(4): 250-263
    The Question of Survival or Death: What Is the Role of Autophagy in Acute Myeloid Leukemia (AML)?
    Atousa Haghi, Mahnaz Mohammadi Kian, Mahdieh Salemi, Mohammad Reza Eghdami, Mohsen Nikbakht.
      Autophagy plays a critical role in balancing sources of energy in response to harsh conditions and nutrient deprivation. Autophagy allows cells to survive in harsh condition and also serve as a death mechanism. Any dysregulation in autophagy signaling may lead to several disorders. Autophagy has been proposed to explain chemotherapy resistance in acute myeloid leukemia (AML). This signaling pathway can either act as a tumor suppressive function or chemo-resistance mechanism. Conventional chemotherapy drugs enhance apoptosis and indicate clinical benefit, but in some cases, relapse and chemotherapy resistance are observed. In leukemia, autophagy may promote cell survival in response to chemotherapy drugs. Therefore, new strategies by inhibiting or activating autophagy may find a broad application for treating leukemia and may significantly enhance clinical outcomes. In this review, we discussed the dimensional role of autophagy in leukemia.
    Keywords:  Acute myeloid leukemia (AML); Autophagy; Cell survival; Chemoresistance
    DOI:  https://doi.org/10.18502/ijhoscr.v16i4.10883
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