bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–02–14
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Mitochondrial dynamics in cancer stem cells.
  2. Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation.
  3. The Stemness-High Human Colorectal Cancer Cells Promote Angiogenesis by Producing Higher Amounts of Angiogenic Cytokines via Activation of the Egfr/Akt/Nf-κB Pathway.
  4. Interleukin (IL)-24: Reconfiguring the Tumor Microenvironment for Eliciting Antitumor Response.
  5. Endothelial Nitric Oxide Synthase Knockdown in Human Stem Cells Impacts Mitochondrial Biogenesis and Adipogenesis: Live-Cell Real-Time Fluorescence Imaging.
  6. RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.
  7. Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation.
  8. Mitochondrial reactive oxygen species in physiology and disease.
  9. Combinations using checkpoint blockade to overcome resistance.
  10. Adenylate kinase 2 expression and addiction in T-ALL.
  11. Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li-Fraumeni syndrome.
  12. A narrative review of central nervous system involvement in acute leukemias.
  1. Cell Mol Life Sci. 2021 Feb 13.
    Mitochondrial dynamics in cancer stem cells.
    Dane T Sessions, David F Kashatus.
      Many tumors are now understood to be heterogenous cell populations arising from a minority of epithelial-like cancer stem cells (CSCs). CSCs demonstrate distinctive metabolic signatures from the more differentiated surrounding tumor bulk that confer resistance to traditional chemotherapeutic regimens and potential for tumor relapse. Many CSC phenotypes including metabolism, epithelial-to-mesenchymal transition, cellular signaling pathway activity, and others, arise from altered mitochondrial function and turnover, which are regulated by constant cycles of mitochondrial fusion and fission. Further, recycling of mitochondria through mitophagy in CSCs is associated with maintenance of reactive oxygen species levels that dictate gene expression. The protein machinery that drives mitochondrial dynamics is surprisingly simple and may represent attractive new therapeutic avenues to target CSC metabolism and selectively eradicate tumor-generating cells to reduce the risks of metastasis and relapse for a variety of tumor types.
    Keywords:  Cancer stem cells; EMT; Metabolism; Mitochondrial dynamics; Mitochondrial morphology; Signaling; Therapeutic resistance
    DOI:  https://doi.org/10.1007/s00018-021-03773-2
  2. Cell Stem Cell. 2021 Feb 01. pii: S1934-5909(21)00006-0. [Epub ahead of print]
    Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation.
    Keane Jared Guillaume Kenswil, Paola Pisterzi, Gonzalo Sánchez-Duffhues, Claire van Dijk, Andrea Lolli, Callie Knuth, Byambasuren Vanchin, Adrian Christopher Jaramillo, Remco Michiel Hoogenboezem, Mathijs Arnoud Sanders, Jacqueline Feyen, Tom Cupedo, Ivan G Costa, Ronghui Li, Eric Moniqué Johannes Bindels, Kirsten Lodder, Bianca Blom, Pieter Koen Bos, Marie-José Goumans, Peter Ten Dijke, Eric Farrell, Guido Krenning, Marc Hermanus Gerardus Petrus Raaijmakers.
      Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.
    Keywords:  EndoMT; development; endothelial; endothelial-mesenchymal transition; hematopoietic stem cell; mesenchymal; niche; regeneration; stroma; transdifferentiation
    DOI:  https://doi.org/10.1016/j.stem.2021.01.006
  3. Int J Mol Sci. 2021 Jan 29. pii: 1355. [Epub ahead of print]22(3):
    The Stemness-High Human Colorectal Cancer Cells Promote Angiogenesis by Producing Higher Amounts of Angiogenic Cytokines via Activation of the Egfr/Akt/Nf-κB Pathway.
    Shin-Yi Chung, Ta-Chung Chao, Yeu Su.
       PURPOSE: Cancer stem cells (CSCs) are responsible for cancer metastasis by stimulating tumor angiogenesis via various mechanisms. To elucidate the potential of the stemness-high human colorectal cancer (CRC) cells (i.e., CRCSCs) in activating angiogenesis, effects of the GATA6-overexpressing HCT-116 and HT-29 human CRC clones established previously by us in promoting the angiogenesis of human umbilical vein endothelial cells (HUVECs) were examined.
    METHODS: Angiogenesis-promoting effects (i.e., migration, invasion, DNA synthesis, and tube formation) in HUVECs of the conditioned media (CM) from various human CRC clones were analyzed. MMP activities were assessed using a zymography assay. Western blotting and selective inhibitors were used to dissect the signaling pathway involved. IHC was used to examine the vascular density in tumor xenografts.
    RESULTS: We found that the conditioned media (CM) collected from the GATA6-overexpressing clones enhanced angiogenesis of HUVECs more effectively which might be attributed partly to a higher MMP-9 production by HUVECs. Subsequently, elevated levels of IL-8 and VEGF-A were detected in the CM whose tube formation-enhancing activities were abolished by the co-treatment with either a VEGFR2 inhibitor or an IL-8 neutralizing antibody. Interestingly, increased production of these cytokines in the GATA6-overexpressing clones was due to an EGFR/AKT-mediated activation of NF-κB. Furthermore, not only were the levels of CD31 and endomucin but also the blood vessel density was much higher in the xenograft tumors grown from these clones.
    CONCLUSION: Our findings demonstrate that human CRCSCs promote a stronger angiogenesis by producing higher amounts of angiogenic factors through activation of the EGFR/AKT/NF-κB pathway.
    Keywords:  EGFR; GATA6; NF-κB; angiogenesis; colorectal cancer stem cell
    DOI:  https://doi.org/10.3390/ijms22031355
  4. Adv Exp Med Biol. 2021 ;1290 99-110
    Interleukin (IL)-24: Reconfiguring the Tumor Microenvironment for Eliciting Antitumor Response.
    Rajagopal Ramesh, Rebaz Ahmed, Anupama Munshi.
      Interleukin (IL)-24 is a member of the IL-10 family of cytokines. Due to its unique ability to function as both a tumor suppressor and cytokine, IL-24-based cancer therapy has been developed for treating a broad spectrum of human cancers. Majority of the studies reported to date have focused on establishing IL-24 as a cancer therapeutic by primarily focusing on tumor cell killing. However, the ability of IL-24 treatment on modulating the tumor microenvironment and immune response is underinvestigated. In this article, we summarize the biological and functional properties of IL-24 and the benefits of applying IL-24-based therapy for cancer.
    Keywords:  Angiogenesis; Apoptosis; Cancer; Cancer stem cells; Cytokines; Glycosylation; IL-10; IL-19; IL-20 receptor; IL-22 receptor; IL-24; Immunity; Metastasis; Phosphorylation; Post-translational modification; Ubiquitination; mda-7
    DOI:  https://doi.org/10.1007/978-3-030-55617-4_7
  5. J Clin Med. 2021 Feb 07. pii: 631. [Epub ahead of print]10(4):
    Endothelial Nitric Oxide Synthase Knockdown in Human Stem Cells Impacts Mitochondrial Biogenesis and Adipogenesis: Live-Cell Real-Time Fluorescence Imaging.
    Sylvia Lee-Huang, Philip Lin Huang, Paul Lee Huang.
      We carried out live-cell real-time fluorescence imaging to follow the effects of genetic (siRNA) knockdown (KD) of endothelial nitric oxide synthase (eNOS) on mitochondrial biogenesis and adipogenesis in human mesenchymal stem cells (hMSCs). We report here that eNOS KD in hMSCs blocks mitochondrial biogenesis and adipogenesis. The transfer of mitochondria from normal hMSCs to eNOS-deficient hMSCs restores adipogenesis. Furthermore, cell-free mitochondria purified from normal hMSCs also restores adipogenesis in eNOS-deficient cells. Thus, eNOS and NO signaling are essential for mitochondrial biogenesis, and mitochondrial activity is indispensable for adipogenesis in hMSC differentiation. We mapped the path and identified the mechanisms of mitochondrial transfer. We captured real-time images of differentiated mature adipocytes in mitosis and replication. These results reveal that human stem cell-differentiated fat cells are capable of replication. This new finding offers novel insights into our understanding of fat cell expansion and the development of obesity. Real-time imaging in live cells allows synchronized investigation of mitochondrial biogenesis and adipogenesis in stem cell differentiation without reducing living cells to nonliving samples for functional analysis. Live-cell real-time imaging can thus be a faithful and immediate tool for molecular diagnostic medicine. Furthermore, our results suggest that mitochondrial remodeling can be a useful approach in treating adiposity, diabetes, and abnormalities in energy metabolism and vascular signaling.
    Keywords:  adipogenesis; endothelial nitric oxide synthase (eNOS); human mesenchymal stem cell (hMSC); live-cell real-time fluorescence imaging; mitochondrial biogenesis; mitochondrial remodeling; molecular diagnostic medicine; nitric oxide (NO)
    DOI:  https://doi.org/10.3390/jcm10040631
  6. J Clin Invest. 2021 Feb 02. pii: 141566. [Epub ahead of print]
    RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.
    Filip Matthijssens, Nitesh D Sharma, Monique Nysus, Christian K Nickl, Huining Kang, Dominique R Perez, Beatrice Lintermans, Wouter Van Loocke, Juliette Roels, Sofie Peirs, Lisa Demoen, Tim Pieters, Lindy Reunes, Tim Lammens, Barbara De Moerloose, Filip Van Nieuwerburgh, Dieter L Deforce, Laurence C Cheung, Rishi S Kotecha, Martijn D P Risseeuw, Serge Van Calenbergh, Takeshi Takarada, Yukio Yoneda, Frederik W van Delft, Richard B Lock, Seth D Merkley, Alexandre Chigaev, Larry A Sklar, Charles G Mullighan, Mignon L Loh, Stuart S Winter, Stephen P Hunger, Steven Goossens, Eliseo F Castillo, Wojciech Ornatowski, Pieter Van Vlierberghe, Ksenia Matlawska-Wasowska.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared to B-cell ALL. Here, we showed that Runt-related transcription factor 2, RUNX2 was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We reported direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrated that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its co-factor CBFβ. In conclusion, we showed that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumour metabolism and leukemic cell migration.
    Keywords:  Cell migration/adhesion; Leukemias; Molecular biology; Oncology
    DOI:  https://doi.org/10.1172/JCI141566
  7. Oncogene. 2021 Feb 09.
    Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation.
    Yongjie Ma, Junyi Zha, XiangKun Yang, Qianjin Li, Qingfu Zhang, Amelia Yin, Zanna Beharry, Hanwen Huang, Jiaoti Huang, Michael Bartlett, Kaixiong Ye, Hang Yin, Houjian Cai.
      Fatty acid metabolism is essential for the biogenesis of cellular components and ATP production to sustain proliferation of cancer cells. Long-chain fatty acyl-CoA synthetases (ACSLs), a group of rate-limiting enzymes in fatty acid metabolism, catalyze the bioconversion of exogenous or de novo synthesized fatty acids to their corresponding fatty acyl-CoAs. In this study, systematical analysis of ACSLs levels and the amount of fatty acyl-CoAs illustrated that ACSL1 were significantly associated with the levels of a broad spectrum of fatty acyl-CoAs, and were elevated in human prostate tumors. ACSL1 increased the biosynthesis of fatty acyl-CoAs including C16:0-, C18:0-, C18:1-, and C18:2-CoA, triglycerides and lipid accumulation in cancer cells. Mechanistically, ACSL1 modulated mitochondrial respiration, β-oxidation, and ATP production through regulation of CPT1 activity. Knockdown of ACSL1 inhibited the cell cycle, and suppressed the proliferation and migration of prostate cancer cells in vitro, and growth of prostate xenograft tumors in vivo. Our study implicates ACSL1 as playing an important role in prostate tumor progression, and provides a therapeutic strategy of targeting fatty acid metabolism for the treatment of prostate cancer.
    DOI:  https://doi.org/10.1038/s41388-021-01667-y
  8. Cell Calcium. 2021 Jan 02. pii: S0143-4160(20)30186-X. [Epub ahead of print]94 102344
    Mitochondrial reactive oxygen species in physiology and disease.
    Salvatore Antonucci, Fabio Di Lisa, Nina Kaludercic.
      Mitochondrial reactive oxygen species (mROS) are routinely produced at several sites within the organelle. The balance in their formation and elimination is maintained by a complex and robust antioxidant system. mROS may act as second messengers and regulate a number of physiological processes, such as insulin signaling, cell differentiation and proliferation, wound healing, etc. Nevertheless, when a sudden or sustained increase in ROS formation is not efficiently neutralized by the endogenous antioxidant defense system, the detrimental impact of high mROS levels on cell function and viability eventually results in disease development. In this review, we will focus on the dual role of mROS in pathophysiology, emphasizing the physiological role exerted by a regulated mROS production/elimination, and discussing the detrimental effects evoked by an imbalance in mitochondrial redox state. Furthermore, we will touch upon the interplay between mROS and Ca2+ homeostasis.
    Keywords:  Calcium; Mitochondria; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.ceca.2020.102344
  9. Ecancermedicalscience. 2020 ;14 1148
    Combinations using checkpoint blockade to overcome resistance.
    Stefania Morganti, Giuseppe Curigliano.
      The advent of immunotherapy for cancer represented a paradigm shift in the treatment approach of neoplasia. Immune-checkpoint inhibitors (ICIs) were demonstrated to significantly improve outcomes, including overall survival across several cancer types, with yearly-durable responses. Nevertheless, many patients derive minor or no benefit with immune checkpoint (IC)-blockade, including patients with cancer types traditionally considered immunogenic. Combination strategies of ICIs with chemotherapy, radiotherapy, targeted therapies or other immunotherapy compounds have been conceived in order to boost the immune-responses and potentially overcome resistance to ICIs. This review focuses on mechanisms underlying resistance to IC-blockade and provides an overview of potential advantages and limitations of combination strategies currently under investigation.
    Keywords:  NGIM; chemo-immunotherapy; immune-checkpoint inhibitors; immunotherapy combinations; immunotherapy resistance; next-generation immune modulators; targeted therapy
    DOI:  https://doi.org/10.3332/ecancer.2020.1148
  10. Blood Adv. 2021 Feb 09. 5(3): 700-710
    Adenylate kinase 2 expression and addiction in T-ALL.
    Nabih Maslah, Mehdi Latiri, Vahid Asnafi, Mélanie Féroul, Nawel Bedjaoui, Thomas Steimlé, Emmanuelle Six, Els Verhoyen, Elizabeth Macintyre, Chantal Lagresle-Peyrou, Ludovic Lhermitte, Guillaume P Andrieu.
      T-cell acute lymphoblastic leukemia (T-ALL) represents the malignant expansion of immature T cells blocked in their differentiation. T-ALL is still associated with a poor prognosis, mainly related to occurrence of relapse or refractory disease. A critical medical need therefore exists for new therapies to improve the disease prognosis. Adenylate kinase 2 (AK2) is a mitochondrial kinase involved in adenine nucleotide homeostasis recently reported as essential in normal T-cell development, as defective AK2 signaling pathway results in a severe combined immunodeficiency with a complete absence of T-cell differentiation. In this study, we show that AK2 is constitutively expressed in T-ALL to varying levels, irrespective of the stage of maturation arrest or the underlying oncogenetic features. T-ALL cell lines and patient T-ALL-derived xenografts present addiction to AK2, whereas B-cell precursor ALL cells do not. Indeed, AK2 knockdown leads to early and massive apoptosis of T-ALL cells that could not be rescued by the cytosolic isoform AK1. Mechanistically, AK2 depletion results in mitochondrial dysfunction marked by early mitochondrial depolarization and reactive oxygen species production, together with the depletion of antiapoptotic molecules (BCL-2 and BCL-XL). Finally, T-ALL exposure to a BCL-2 inhibitor (ABT-199 [venetoclax]) significantly enhances the cytotoxic effects of AK2 depletion. We also show that AK2 depletion disrupts the oxidative phosphorylation pathway. Combined with pharmaceutical inhibition of glycolysis, AK2 silencing prevents T-ALL metabolic adaptation, resulting in dramatic apoptosis. Altogether, we pinpoint AK2 as a genuine and promising therapeutic target in T-ALL.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002700
  11. Leukemia. 2021 Feb 12.
    Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li-Fraumeni syndrome.
    Greta Winter, Renate Kirschner-Schwabe, Stefanie Groeneveld-Krentz, Gabriele Escherich, Anja Möricke, Arend von Stackelberg, Martin Stanulla, Simon Bailey, Lisa Richter, Doris Steinemann, Tim Ripperger, Adela Escudero, Roula Farah, Olli Lohi, Karin Wadt, Marjolijn Jongmans, Nienke van Engelen, Cornelia Eckert, Christian Peter Kratz.
      
    DOI:  https://doi.org/10.1038/s41375-021-01163-y
  12. Ann Transl Med. 2021 Jan;9(1): 68
    A narrative review of central nervous system involvement in acute leukemias.
    Dalma Deak, Nicolae Gorcea-Andronic, Valentina Sas, Patric Teodorescu, Catalin Constantinescu, Sabina Iluta, Sergiu Pasca, Ionut Hotea, Cristina Turcas, Vlad Moisoiu, Alina-Andreea Zimta, Simona Galdean, Jakob Steinheber, Ioana Rus, Sebastian Rauch, Cedric Richlitzki, Raluca Munteanu, Ancuta Jurj, Bobe Petrushev, Cristina Selicean, Mirela Marian, Olga Soritau, Alexandra Andries, Andrei Roman, Delia Dima, Alina Tanase, Olafur Sigurjonsson, Ciprian Tomuleasa.
      Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although asymptomatic or with unspecific symptoms, CNS leukemia should be assessed in both AML/ALL patients, through a combination of flow cytometry and cytological analysis of CSF. Intrathecal therapy (ITT) is a preventive measure for CNS involvement in AML and ALL, still much research is needed in finding the appropriate target that would dramatically lower CNS involvement in acute leukemia.
    Keywords:  Acute leukemias; central nervous system involvement (CNS involvement); clinical management; pathophysiology
    DOI:  https://doi.org/10.21037/atm-20-3140
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