bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–04–03
fourteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.
  2. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
  3. Cutting the umbilical cord: Cancer stem cell-targeted therapeutics.
  4. Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy.
  5. B cells regulate hematopoietic stem cells via cholinergic signaling.
  6. Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells.
  7. Uncovering Pharmacological Opportunities for Cancer Stem Cells-A Systems Biology View.
  8. Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment.
  9. Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction.
  10. Metabolic regulation of CD8+ T cells: from mechanism to therapy.
  11. The Interplay Between TGF-β Signaling and Cell Metabolism.
  12. Venetoclax enhances DNA damage induced by XPO1 inhibitors: A novel mechanism underlying the synergistic antileukaemic effect in acute myeloid leukaemia.
  13. Citrate transporter inhibitors: possible new anticancer agents.
  14. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia.
  1. Br J Pharmacol. 2022 Mar 30.
    Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.
    Xinrong Xiang, Rui Bao, Yu Wu, Youfu Luo.
      Targeting cancer metabolism has emerged as an attractive approach to improve therapeutic regimens in acute myeloid leukemia (AML). Mitochondrial proteases are closely related to cancer metabolism, but their biological functions have not been well characterized in AML. According to different catogory, we comprehensively reviewed the role of mitochondrial proteases in AML. This review highlights some 'powerful' mitochondrial protease targets, including their biological function, chemical modulators, and applicative prospect in AML.
    Keywords:  acute myeloid leukemia; mitochondrial metabolism; mitochondrial proteases; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/bph.15844
  2. Exp Cell Res. 2022 Mar 25. pii: S0014-4827(22)00105-7. [Epub ahead of print]415(1): 113112
    IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
    Yanjie Zhang, Hezhou Guo, Zhaoli Zhang, Wei Lu, Jiang Zhu, Jun Shi.
      Chemoresistance contributes to poor survival and high relapse risk in acute myeloid leukemia (AML). As a pro-inflammatory cytokine, interleukin-6 (IL-6) plays a vital role in the chemoresistance of malignancies. However, the underlying mechanisms of chemoresistance in AML have not been widely studied. Lipid metabolism, which contributes to chemoresistance in AML, is enhanced by IL-6 in skeletal muscle cells. We hypothesized that IL-6 promotes the chemoresistance of AML by promoting lipid metabolism. Based on the positive correlation between IL-6 receptor expression and the cellular response to exogenous IL-6, we performed Gene Ontology analysis of a dataset consisting the information of 151 AML patients from The Cancer Genome Atlas. We found that lipid transport-associated genes were upregulated in the high IL-6 receptor expression group. Additionally, IL-6 promoted fatty acid (FA) uptake in both AML cell lines and primary AML cells. Inhibition of FA uptake by sulfo-N-succinimidyl oleate repressed IL-6-induced chemoresistance. Western blotting, quantitative polymerase chain reaction, and chromatin immunoprecipitation assays indicated that IL-6 promoted CD36 expression at both the mRNA and protein levels through stat3 signaling. Knockout of CD36 or stat3 repressed IL-6-induced FA uptake and chemoresistance. Furthermore, in five human AML samples, we validated that compared to CD36-cells, CD36+ primary AML cells were less sensitive to cytosine arabinoside (Ara-c) and that blockade of CD36 re-sensitized CD36+ AML cells to Ara-c. Mice injected with CD36 knockout cells followed by treatment with Ara-c showed markedly decreased leukemia burden and prolonged survival in vivo. Finally, treatment with the CD36 antibody in combination with Ara-c exhibited synergistic effects in vivo. In conclusion, IL-6 promotes chemoresistance in AML through the stat3/CD36-mediated FA uptake. Blockade of CD36 improved the effect of Ara-c, representing a promising strategy for AML therapy.
    Keywords:  Acute myeloid leukemia; CD36; Chemoresistance; Fatty acid uptake; Interleukin-6
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113112
  3. Life Sci. 2022 Mar 26. pii: S0024-3205(22)00202-8. [Epub ahead of print] 120502
    Cutting the umbilical cord: Cancer stem cell-targeted therapeutics.
    Ankit Banik, Rishika Sharma, Akansha Chauhan, Sandhya Singh.
      Cancer Stem Cells (CSCs) are a notoriously quiescent subpopulation of cells within heterogeneous tumors exhibiting self-renewal, differentiation and drug-resistant capabilities leading to tumour relapse. Heterogeneous cell populations in tumour microenvironment develop an elaborate network of signalling and factors supporting the CSC population within a niche. Identification of specific biomarkers for CSCs facilitates their isolation. CSCs demonstrate abilities that bypass immune surveillance, exhibit resistance to therapy, and induce cancer recurrence while promoting altered metabolism of the bulk tumour, thereby encouraging metastasis. The fight against cancer is prone to relapse without discussing the issue of CSCs, making it imperative for encapsulation of current studies. In this review, we provide extensive knowledge of recent therapeutics developed that target CSCs via multiple signalling cascades, altered metabolism and the tumour microenvironment. Thorough understanding of the functioning of CSCs, their interaction with different cells in the tumour microenvironment as well as current gaps in knowledge are addressed. We present possible strategies to disrupt the cellular and molecular interplay within the tumour microenvironment and make it less conducive for CSCs, which may aid in their eradication with subsequently better treatment outcomes. In conclusion, we discuss a brief yet functional idea of emerging concepts in CSC biology to develop efficient therapeutics acting on cancer recurrence and metastasis.
    Keywords:  Biomarkers; Cancer microenvironment; Cancer stem cell; Metabolism; Signalling; Therapeutics
    DOI:  https://doi.org/10.1016/j.lfs.2022.120502
  4. Clin Transl Med. 2022 Mar;12(3): e645
    Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy.
    Sona Stemberkova-Hubackova, Renata Zobalova, Maria Dubisova, Jana Smigova, Sarka Dvorakova, Klara Korinkova, Zuzana Ezrova, Berwini Endaya, Kristyna Blazkova, Erik Vlcak, Petra Brisudova, Dan-Diem Thi Le, Stefan Juhas, Daniel Rosel, Cristina Daniela Kelemen, Dana Sovilj, Eliska Vacurova, Tomas Cajka, Vlada Filimonenko, Lanfeng Dong, Ladislav Andera, Pavel Hozak, Jan Brabek, Zuzana Bielcikova, Jan Stursa, Lukas Werner, Jiri Neuzil.
      
    DOI:  https://doi.org/10.1002/ctm2.645
  5. Nat Immunol. 2022 Mar 28.
    B cells regulate hematopoietic stem cells via cholinergic signaling.
    Sweta B Patel, Eric M Pietras.
      
    DOI:  https://doi.org/10.1038/s41590-022-01172-8
  6. Clin Cancer Res. 2022 Mar 29. pii: clincanres.3594.2021. [Epub ahead of print]
    Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells.
    Giulia Corradi, Barbara Bassani, Giorgia Simonetti, Sabina Sangaletti, Jayakumar Vadakekolathu, Maria Chiara Fontana, Martina Pazzaglia, Alessandro Gulino, Claudio Tripodo, Gianluca Cristiano, Lorenza Bandini, Emanuela Ottaviani, Darina Ocadlikova, Milena Piccioli, Giovanni Martinelli, Mario Paolo Colombo, Sergio Rutella, Michele Cavo, Marilena Ciciarello, Antonio Curti.
       PURPOSE: The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis.
    EXPERIMENTAL DESIGN: BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone.
    RESULTS: IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment.
    CONCLUSIONS: IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3594
  7. Front Cell Dev Biol. 2022 ;10 752326
    Uncovering Pharmacological Opportunities for Cancer Stem Cells-A Systems Biology View.
    Cristina Correia, Taylor M Weiskittel, Choong Yong Ung, Jose C Villasboas Bisneto, Daniel D Billadeau, Scott H Kaufmann, Hu Li.
      Cancer stem cells (CSCs) represent a small fraction of the total cancer cell population, yet they are thought to drive disease propagation, therapy resistance and relapse. Like healthy stem cells, CSCs possess the ability to self-renew and differentiate. These stemness phenotypes of CSCs rely on multiple molecular cues, including signaling pathways (for example, WNT, Notch and Hedgehog), cell surface molecules that interact with cellular niche components, and microenvironmental interactions with immune cells. Despite the importance of understanding CSC biology, our knowledge of how neighboring immune and tumor cell populations collectively shape CSC stemness is incomplete. Here, we provide a systems biology perspective on the crucial roles of cellular population identification and dissection of cell regulatory states. By reviewing state-of-the-art single-cell technologies, we show how innovative systems-based analysis enables a deeper understanding of the stemness of the tumor niche and the influence of intratumoral cancer cell and immune cell compositions. We also summarize strategies for refining CSC systems biology, and the potential role of this approach in the development of improved anticancer treatments. Because CSCs are amenable to cellular transitions, we envision how systems pharmacology can become a major engine for discovery of novel targets and drug candidates that can modulate state transitions for tumor cell reprogramming. Our aim is to provide deeper insights into cancer stemness from a systems perspective. We believe this approach has great potential to guide the development of more effective personalized cancer therapies that can prevent CSC-mediated relapse.
    Keywords:  cancer stem cells; cellular niche; drug resistance; immunotherapy; systems biology; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2022.752326
  8. Pflugers Arch. 2022 Mar 28.
    Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment.
    Jieun Seo, Jeong-Eun Yun, Sung Joon Kim, Yang-Sook Chun.
      Cancer cells rewire metabolic processes to adapt to the nutrient- and oxygen-deprived tumour microenvironment, thereby promoting their proliferation and metastasis. Previous research has shown that modifying glucose metabolism, the Warburg effect, makes glycolytic cancer cells more invasive and aggressive. Lipid metabolism has also been receiving attention because lipids function as energy sources and signalling molecules. Because obesity is a risk factor for various cancer types, targeting lipid metabolism may be a promising cancer therapy. Here, we review the lipid metabolic reprogramming in cancer cells mediated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is the master transcription factor for tumour growth and metastasis by transactivating genes related to proliferation, survival, angiogenesis, invasion, and metabolism. The glucose metabolic shift (the Warburg effect) is mediated by HIF-1. Recent research on HIF-1-related lipid metabolic reprogramming in cancer has confirmed that HIF-1 also modifies lipid accumulation, β-oxidation, and lipolysis in cancer, triggering its progression. Therefore, targeting lipid metabolic alterations by HIF-1 has therapeutic potential for cancer. We summarize the role of the lipid metabolic shift mediated by HIF-1 in cancer and its putative applications for cancer therapy.
    Keywords:  Cancer therapy; Hypoxia-inducible factor-1; Lipid metabolism; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s00424-022-02683-x
  9. Biochem Biophys Res Commun. 2022 Mar 17. pii: S0006-291X(22)00419-3. [Epub ahead of print]606 61-67
    Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction.
    Leandro Henrique de Paula Assis, Gabriel de Gabriel Dorighello, Helena Coutinho Franco de Oliveira.
      Macrophages play a role in host defense, tissue remodeling and inflammation. Different inflammatory stimuli drive macrophage phenotypes and responses. In this study we investigated the relationship between macrophages immune phenotype and mitochondrial bioenergetics, cell redox state and endoplasmic reticulum (ER)-mitochondria interaction. Bacterial lipopolysaccharide (LPS) and interferon-γ (IFNγ) pro-inflammatory stimuli decreased oxidative metabolism (basal, phosphorylating and maximal conditions) and increased baseline glycolysis (117%) and glycolytic capacity (43%) in THP-1 macrophages. In contrast, interleukin-4 (IL4) and interleukin-13 (IL13) anti-inflammatory stimuli increased the oxygen consumption rates in baseline conditions (21%) and associated with ATP production (19%). LPS + IFNγ stimuli reduced superoxide anion levels by accelerating its conversion into hydrogen peroxide (H2O2) while IL4+IL13 decreased H2O2 release rates. The source of these oxidants was extra-mitochondrial and associated with increased NOX2 and SOD1 gene expression. LPS + IFNγ stimuli decreased ER-mitochondria contact sites as measured by IP3R1-VDAC1 interaction (34%) and markedly upregulated genes involved in mitochondrial fusion (9-10 fold, MFN1 and 2) and fission (∼7 fold, DRP1 and FIS1). Conversely, IL4+IL13 stimuli did not altered ER-mitochondria interactions nor MFN1 and 2 expression. Together, these results unveil ER-mitochondria interaction pattern as a novel feature of macrophage immunological, metabolic and redox profiles.
    Keywords:  Endoplasmic reticulum-mitochondria interaction; Macrophage; Mitochondrial respiration; Oxidants production
    DOI:  https://doi.org/10.1016/j.bbrc.2022.03.086
  10. Antioxid Redox Signal. 2022 Mar 29.
    Metabolic regulation of CD8+ T cells: from mechanism to therapy.
    Ying Zheng, Xiaomin Wang, Min Huang.
       SIGNIFICANCE: Cancer immunotherapy has yielded striking anti-tumor effects in many cancers, yet the proportion of benefited patients are still limited. As key mediators of tumor suppression, CD8+ T cells are crucial for cancer immunotherapy. It has been widely appreciated that modulation of CD8+ T cell immunity could be an effective way to further improve the therapeutic benefit of immunotherapy.
    RECENT ADVANCES: Emerging evidence has underlined a close link between metabolism and immune functions, providing a metabolism-immune axis that is increasingly investigated for understanding CD8+ T cells regulation. On the other hand, growing findings have reported that tumors adopt multiple approaches to induce metabolic reprogramming of CD8+ T cells, leading to the compromised immunotherapy.
    CRITICAL ISSUES: CD8+ T cell metabolism in the tumor microenvironment (TME) is often adapted to diminish anti-tumor immune responses and thereby evade from immune surveillance. A better understanding of metabolic regulation of CD8+ T cells in the TME is believed to hold promise for opening a new therapeutic window to further improve the benefit of immunotherapy. We herein review the mechanistic understanding of how CD8+ T cell metabolism is reprogrammed in the TME, mainly focusing on the impact of nutrient availability and bioactive molecules secreted by surrounding cells.
    FUTURE DIRECTIONS: Future research should pay attention to tumor heterogeneity in the metabolic microenvironment and associated immune responses. It is also important to include the trending opinion of "precision medicine" in cancer immunotherapies to tailor metabolic interventions for individual patients in combination with immunotherapy treatments.
    DOI:  https://doi.org/10.1089/ars.2022.0040
  11. Front Cell Dev Biol. 2022 ;10 846723
    The Interplay Between TGF-β Signaling and Cell Metabolism.
    Huidong Liu, Ye-Guang Chen.
      The transforming growth factor-β (TGF-β) signaling plays a critical role in the development and tissue homeostasis in metazoans, and deregulation of TGF-β signaling leads to many pathological conditions. Mounting evidence suggests that TGF-β signaling can actively alter metabolism in diverse cell types. Furthermore, metabolic pathways, beyond simply regarded as biochemical reactions, are closely intertwined with signal transduction. Here, we discuss the role of TGF-β in glucose, lipid, amino acid, redox and polyamine metabolism with an emphasis on how TGF-β can act as a metabolic modulator and how metabolic changes can influence TGF-β signaling. We also describe how interplay between TGF-β signaling and cell metabolism regulates cellular homeostasis as well as the progression of multiple diseases, including cancer.
    Keywords:  Smad; TGF-β signaling; amino acid metabolism; glucose metabolism; lipid metabolism
    DOI:  https://doi.org/10.3389/fcell.2022.846723
  12. J Cell Mol Med. 2022 Mar 31.
    Venetoclax enhances DNA damage induced by XPO1 inhibitors: A novel mechanism underlying the synergistic antileukaemic effect in acute myeloid leukaemia.
    Hanxi Yu, Shuangshuang Wu, Shuang Liu, Xinyu Li, Yuqing Gai, Hai Lin, Yue Wang, Holly Edwards, Yubin Ge, Guan Wang.
      Acute myeloid leukaemia (AML) is a highly heterogeneous haematologic malignancy with poor prognosis. We previously showed synergistic antileukaemic interaction between exportin 1 (XPO1) inhibitor KPT-330 (Selinexor) and Bcl-2 inhibitor venetoclax (ABT-199) in preclinical models of AML, which was partially meditated by Mcl-1, although the full mechanism of action remains unknown. In this study, using real-time RT-PCR and Western blot analysis, we show that inhibition of XPO1 via KPT-330 or KPT-8602 (Eltanexor) decreases the mRNA and protein levels of c-Myc, CHK1, WEE1, RAD51 and RRM2. KPT-330 and KPT-8602 induce DNA damage, as determined by alkaline comet assay. In addition, we demonstrate that venetoclax enhances KPT-330- and KPT-8602-induced DNA damage, likely through inhibition of DNA damage repair. This study provides new insight into the molecular mechanism underlying the synergistic antileukaemic activity between venetoclax and XPO1 inhibitors against AML. Our data support the clinical evaluation of this promising combination therapy for the treatment of AML.
    Keywords:  DNA damage; XPO1 inhibitor; acute myeloid leukaemia; combination treatment; venetoclax
    DOI:  https://doi.org/10.1111/jcmm.17274
  13. Future Med Chem. 2022 Mar 31.
    Citrate transporter inhibitors: possible new anticancer agents.
    Shivaputra A Patil, June A Mayor, Ronald S Kaplan.
      The culmination of 80+ years of cancer research implicates the aberrant metabolism in tumor cells as a root cause of pathogenesis. Citrate is an essential molecule in intermediary metabolism, and its amplified availability to critical pathways in cancer cells via citrate transporters confers a high rate of cancer cell growth and proliferation. Inhibiting the plasma membrane and mitochondrial citrate transporters - whether individually, in combination, or partnered with complementary metabolic targets - in order to combat cancer may prove to be a consequential chemotherapeutic strategy. This review aims to summarize the use of different classes of citrate transporter inhibitors for anticancer activity, either individually or as part of a cocktail.
    Keywords:  anticancer; citrate; drug discovery; mitochondrial citrate transporter (CTP); plasma membrane citrate transporter (PMCT)
    DOI:  https://doi.org/10.4155/fmc-2021-0341
  14. Leukemia. 2022 Mar 30.
    RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia.
    Justine Decroocq, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, Laury Poulain, Chloe Friedrich, Anne-Sophie Alary, Helene Guermouche, Ambrine Sahal, Guillemette Fouquet, Mathilde Gotanègre, Federico Simonetta, Sarah Mouche, Pierre Gestraud, Auriane Lescure, Elaine Del Nery, Claudie Bosc, Adrien Grenier, Fetta Mazed, Johanna Mondesir, Nicolas Chapuis, Liza Ho, Aicha Boughalem, Marc Lelorc'h, Camille Gobeaux, Michaela Fontenay, Christian Recher, Norbert Vey, Arnaud Guillé, Daniel Birnbaum, Olivier Hermine, Isabelle Radford-Weiss, Petros Tsantoulis, Yves Collette, Rémy Castellano, Jean-Emmanuel Sarry, Eric Pasmant, Didier Bouscary, Olivier Kosmider, Jerome Tamburini.
      Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS, and PTPN11 genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML.
    DOI:  https://doi.org/10.1038/s41375-022-01541-0
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