bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–07–25
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Nuclear NAD+ homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells.
  2. Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells.
  3. Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.
  4. The Role of Amino Acids in the Crosstalk Between Mesenchymal Stromal Cells and Neoplastic Cells in the Hematopoietic Niche.
  5. Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy.
  6. Catch me if you can: how AML and its niche escape immunotherapy.
  7. Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?
  8. How the amino acid leucine activates the key cell-growth regulator mTOR.
  9. Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.
  10. A novel epigenetic drug conjugating flavonoid and HDAC inhibitor confers to suppression of acute myeloid leukemogenesis.
  11. Amino acid metabolism as a therapeutic target in cancer: a review.
  12. Evaluation of pretreatment telomere length as a prognostic marker in intermediate-risk acute myeloid leukemia.
  1. Sci Adv. 2021 Jul;pii: eabf3895. [Epub ahead of print]7(30):
    Nuclear NAD+ homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells.
    Xiangguo Shi, Yajian Jiang, Ayumi Kitano, Tianyuan Hu, Rebecca L Murdaugh, Yuan Li, Kevin A Hoegenauer, Rui Chen, Koichi Takahashi, Daisuke Nakada.
      Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD+ metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify NAMPT and NMNAT1 as AML dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, the presence of NAD+ precursors bypassed the dependence of AML on NAMPT but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. Deletion of NMNAT1 reduced nuclear NAD+, activated p53, and increased venetoclax sensitivity. Conversely, increased NAD+ biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, NMNAT1 was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD+ for AML progression and chemoresistance.
    DOI:  https://doi.org/10.1126/sciadv.abf3895
  2. Cancers (Basel). 2021 Jul 13. pii: 3499. [Epub ahead of print]13(14):
    Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells.
    Raquel Luna-Yolba, Justine Marmoiton, Véronique Gigo, Xavier Marechal, Emeline Boet, Ambrine Sahal, Nathalie Alet, Ifat Abramovich, Eyal Gottlieb, Virgile Visentin, Michael R Paillasse, Jean-Emmanuel Sarry.
      Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the anti-tumor response. The modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve the therapy outcome for AML patients. However, the effect of mitochondrial inhibitors on the immune compartment in the context of AML is yet to be explored. Immune checkpoints such as ectonucleotidase CD39 and programmed dead ligand 1 (PD-L1) have been reported to be expressed in AML and linked to chemo-resistance and a poor prognosis. In the present study, we first demonstrated that a novel selective electron transfer chain complex (ETC) I inhibitor, EVT-701, decreased the OxPHOS metabolism of murine and human cytarabine (AraC)-resistant leukemic cell lines. Furthermore, we showed that while AraC induced an immune response regulation by increasing CD39 expression and by reinforcing the interferon-γ/PD-L1 axis, EVT-701 reduced CD39 and PD-L1 expression in vitro in a panel of both murine and human AML cell lines, especially upon AraC treatment. Altogether, this work uncovers a non-canonical function of ETCI in controlling CD39 and PD-L1 immune checkpoints, thereby improving the anti-tumor response in AML.
    Keywords:  AML; Immune checkpoints; OxPHOS
    DOI:  https://doi.org/10.3390/cancers13143499
  3. Cell Stem Cell. 2021 Jul 12. pii: S1934-5909(21)00274-5. [Epub ahead of print]
    Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.
    Amit Subedi, Qiang Liu, Dhanoop M Ayyathan, David Sharon, Severine Cathelin, Mohsen Hosseini, Changjiang Xu, Veronique Voisin, Gary D Bader, Angelo D'Alessandro, Eric R Lechman, John E Dick, Mark D Minden, Jean C Y Wang, Steven M Chan.
      Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.
    Keywords:  NAD metabolism; NAMPT; SREBP signaling; acute myeloid leukemia; dipyridamole; drug screen; fatty acid; leukemic stem cells; lipotoxicity; metabolism
    DOI:  https://doi.org/10.1016/j.stem.2021.06.004
  4. Front Cell Dev Biol. 2021 ;9 714755
    The Role of Amino Acids in the Crosstalk Between Mesenchymal Stromal Cells and Neoplastic Cells in the Hematopoietic Niche.
    Martina Chiu, Giuseppe Taurino, Massimiliano G Bianchi, Ovidio Bussolati.
      Within the bone marrow hematopoietic cells are in close connection with mesenchymal stromal cells (MSCs), which influence the behavior and differentiation of normal or malignant lymphoid and myeloid cells. Altered cell metabolism is a hallmark of cancer, and changes in nutrient pools and fluxes are important components of the bidirectional communication between MSCs and hematological cancer cells. Among nutrients, amino acids play a significant role in cancer progression and chemo-resistance. Moreover, selected types of cancer cells are extremely greedy for glutamine, and significantly deplete the extracellular pool of the amino acid. As a consequence, this influences the behavior of MSCs in terms of either cytokine/chemokine secretion or differentiation potential. Additionally, a direct nutritional interaction exists between MSCs and immune cells. In particular, selected subpopulations of lymphocytes are dependent upon selected amino acids, such as arginine and tryptophan, for full differentiation and competence. This review describes and discusses the nutritional interactions existing in the neoplastic bone marrow niche between MSCs and other cell types, with a particular emphasis on cancer cells and immune cells. These relationships are discussed in the perspective of potential novel therapeutic strategies based on the interference on amino acid metabolism or intercellular fluxes.
    Keywords:  amino acid transport system; arginine; asparagine; bone marrow; glutamine; leukemia; mesenchymal stromal cell; tryptophan
    DOI:  https://doi.org/10.3389/fcell.2021.714755
  5. Cancers (Basel). 2021 Jul 01. pii: 3311. [Epub ahead of print]13(13):
    Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy.
    Hadia Moindjie, Sylvie Rodrigues-Ferreira, Clara Nahmias.
      Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies.
    Keywords:  ROS; Warburg effect; carcinogenesis; metabolic reprogramming; mitochondria; mitochondrial oxidative respiration; mitophagy; mtDNA mutations; oncometabolites; therapy
    DOI:  https://doi.org/10.3390/cancers13133311
  6. Leukemia. 2021 Jul 23.
    Catch me if you can: how AML and its niche escape immunotherapy.
    Sarah Tettamanti, Alice Pievani, Andrea Biondi, Gianpietro Dotti, Marta Serafini.
      In spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.
    DOI:  https://doi.org/10.1038/s41375-021-01350-x
  7. Cancers (Basel). 2021 Jul 03. pii: 3351. [Epub ahead of print]13(13):
    Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?
    Christopher McCann, Emma M Kerr.
      Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical "cell death" machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.
    Keywords:  cancer metabolism; cell death; drug resistance; mitochondria
    DOI:  https://doi.org/10.3390/cancers13133351
  8. Nature. 2021 Jul 21.
    How the amino acid leucine activates the key cell-growth regulator mTOR.
    Tibor Vellai.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-021-01943-7
  9. Blood. 2021 Jul 22. 138(3): 234-245
    Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.
    Jong Bok Lee, Dilshad H Khan, Rose Hurren, Mingjing Xu, Yoosu Na, Hyeonjeong Kang, Sara Mirali, Xiaoming Wang, Marcela Gronda, Yulia Jitkova, Neil MacLean, Andrea Arruda, Zoe Alaniz, Marina Y Konopleva, Michael Andreeff, Mark D Minden, Li Zhang, Aaron D Schimmer.
      Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.
    DOI:  https://doi.org/10.1182/blood.2020009081
  10. Clin Sci (Lond). 2021 Jul 20. pii: CS20210571. [Epub ahead of print]
    A novel epigenetic drug conjugating flavonoid and HDAC inhibitor confers to suppression of acute myeloid leukemogenesis.
    Juan Zhang, Xuefeng Gao, Mingming Wei, Yonghui Li, Guang Yang, Cheng Yang, Li Yu.
      Epigenetic dysregulation has long been identified as a key driver of leukemogenesis in acute myeloid leukemia (AML). However, epigenetic drugs such as histone deacetylase inhibitors (HDACi) targeting epigenetic alterations in AML have obtained only limited clinical efficiency without clear mechanism. Fortunately, we screened out a novel epigenetic agent named Apigenin-Vorinostat-Conjugate (AVC), which provides us a possibility to handle the heterogenous malignancy. Its inhibition on HDACs was presented by HDACs expression, enzyme activity, and histone acetylation level. Its efficacy against AML was detected by cell viability assay and tumor progression of AML mouse model. Apoptosis is the major way causing cell death. We found AVC efficiently suppresses leukemogenesis whereas sparing the normal human cells. Kasumi-1 cells are at least twenty-fold higher sensitive to AVC (IC50=0.024μM) than vorinostat (IC50=0.513μM) and Ara-C (IC50=0.4366μM). Furthermore, it can efficiently regress the tumorigenesis in AML mouse model while keeping the pivotal organs safe, demonstrating a feasibility and favorable safety profile in treatment of AML. Collectively, these pre-clinical data suggest a promising potential utilizing flavonoid-HDACi-conjugate as a next-generation epigenetic drug for clinical therapy against AML.
    Keywords:  Apigenin-vorinostat-conjugate; Epigenetic therapy; HDAC inhibitors; Synergistic function; acute myeloid leukemia
    DOI:  https://doi.org/10.1042/CS20210571
  11. Amino Acids. 2021 Jul 22.
    Amino acid metabolism as a therapeutic target in cancer: a review.
    Molly Endicott, Michael Jones, Jonathon Hull.
      Malignant cells often demonstrate a proliferative advantage when compared to non-malignant cells. However, the rapid growth and metabolism required for survival can also highlight vulnerabilities specific to these malignant cells. One such vulnerability exhibited by cancer is an increased demand for amino acids (AAs), which often results in a dependency on exogenous sources of AAs or requires upregulation of de novo synthesis. These metabolic alterations can be exploited by therapy, which aims to improve treatment outcome and decrease relapse and reoccurrence. One clinically utilised strategy targeting AA dependency is the use of asparaginase in the treatment of acute lymphoblastic leukaemia (ALL), which results in a depletion of exogenous asparagine and subsequent cancer cell death. Examples of other successful strategies include the exploitation of arginine deiminase and methioninase, nutrient restriction of methionine and the inhibition of glutaminase. In this review, we summarise these treatment strategies into three promising avenues: AA restriction, enzymatic depletion and inhibition of metabolism. This review provides an insight into the complexity of metabolism in cancer, whilst highlighting these three current research avenues that have support in both preclinical and clinical settings.
    Keywords:  Amino acids; Asparaginase; Cancer; Metabolism; Oncology
    DOI:  https://doi.org/10.1007/s00726-021-03052-1
  12. Int J Lab Hematol. 2021 Jul 21.
    Evaluation of pretreatment telomere length as a prognostic marker in intermediate-risk acute myeloid leukemia.
    Runxia Gu, Jingjing Cao, Shuning Wei, Xiaoyuan Gong, Ying Wang, Yingchang Mi, Junping Zhang, Shaowei Qiu, Qing Rao, Min Wang, Hui Wei, Jianxiang Wang.
       INTRODUCTION: The current framework for risk stratification is still insufficient for highly heterogeneous intermediate-risk acute myeloid leukemia (IRC-AML), which lacks specific genomic abnormalities.
    METHODS: In order to incorporate novel biomarkers to refine current risk stratification strategies for patients with this subtype, we investigated pretreatment telomere length (TL), which is essential for maintaining genomic stability, in 204 adults with de novo AML (non-acute promyelocytic leukemia).
    RESULTS: We found that TL measured at diagnosis did not decrease with advancing age in 204 patients with AML (R2  = 0.001, P = .695). A multivariate analysis demonstrated that short TL was independently associated with an inferior relapse-free survival (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.48-6.41, P = .003); event-free survival (HR 2.14, 95% CI 1.12-4.08, P = .021); and overall survival (HR 2.26, 95% CI 1.09-4.67, P = .028) in IRC-AML patients. In addition, IRC-AML patients with short TL also exhibited an increased cumulative incidence of hematologic relapse (HR 2.32, 95% CI 1.08-5.26, P = .032).
    CONCLUSION: Short TL is an independent prognostic factor for poor prognosis in patients with IRC-AML and may represent a novel mechanism that links genomic stability and disease progression.
    Keywords:  acute myeloid leukemia; genomic stability; prognosis; risk factor; telomere
    DOI:  https://doi.org/10.1111/ijlh.13665
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