bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021‒04‒11
fifteen papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

  1. Front Oncol. 2021 ;11 632789
    Keywords:  DHODH inhibitor; NAMPT; bone marrow niche; drug resistance; leukemia stem cells; metabolism; oxidative phosphorylation
  2. Front Cell Dev Biol. 2021 ;9 633305
      DNA repair and metabolic pathways are vital to maintain cellular homeostasis in normal human cells. Both of these pathways, however, undergo extensive changes during tumorigenesis, including modifications that promote rapid growth, genetic heterogeneity, and survival. While these two areas of research have remained relatively distinct, there is growing evidence that the pathways are interdependent and intrinsically linked. Therapeutic interventions that target metabolism or DNA repair systems have entered clinical practice in recent years, highlighting the potential of targeting these pathways in cancer. Further exploration of the links between metabolic and DNA repair pathways may open new therapeutic avenues in the future. Here, we discuss the dependence of DNA repair processes upon cellular metabolism; including the production of nucleotides required for repair, the necessity of metabolic pathways for the chromatin remodeling required for DNA repair, and the ways in which metabolism itself can induce and prevent DNA damage. We will also discuss the roles of metabolic proteins in DNA repair and, conversely, how DNA repair proteins can impact upon cell metabolism. Finally, we will discuss how further research may open therapeutic avenues in the treatment of cancer.
    Keywords:  DNA repair; cell metabolism; glycolysis; homologous recombination; non-homologous end-joining; tumor metabolic reprogramming; warburg effect
  3. Mitochondrion. 2021 Mar 31. pii: S1567-7249(21)00045-3. [Epub ahead of print]
      Mitochondrial DNA (mtDNA) copy number alterations occur in acute myeloid leukemia (AML). We evaluated regulation and biological significance of mtDNA copy number in pediatric AML patients (n=123) by qRT-PCR, and in-vitro studies. MtDNA copy number was significantly higher (p<0.001) and an independent predictor of aggressive disease (p=0.006), lower event free survival (p=0.033), and overall survival (p=0.007). Expression of TFAM, POLG, POLRMT, MYC and ND3 were significantly upregulated. In cell lines, PGC1A inhibition decreased mtDNA copy number (p=0.032) while MYC inhibition had no effect (p=0.229). PGC1A may contribute to enhanced mtDNA copy number, which predicts disease aggressiveness and inferior survival outcome.
    Keywords:  Acute Myeloid Leukemia; Biogenesis; Child; MYC; Mitochondrial DNA copy number; PGC1A
  4. Cell Rep. 2021 Apr 06. pii: S2211-1247(21)00269-2. [Epub ahead of print]35(1): 108955
      Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.
    Keywords:  IL-1 family; cell energy metabolism; cytokines; epigenetics; immunometabolism; infection; inflammation; innate immunity; neutrophils; regulatory cytokine; trained immunity
  5. Cell. 2021 Apr 02. pii: S0092-8674(21)00294-4. [Epub ahead of print]
      Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
    Keywords:  branching evolution; cancer driver genes; cancer evolution; intra-tumor heterogeneity; pan-cancer genomics; subclonal reconstruction; tumor phylogeny; whole-genome sequencing
  6. Front Oncol. 2021 ;11 614215
      The indication of hematopoietic stem cell transplantation (HSCT) in acute promyelocytic leukemia (APL) has evolved historically from a widespread use in front-line therapy during the pre-ATRA era to a virtual rejection of this indication for patients treated with modern treatments. HSCT in first complete remission could only be considered for an extremely small fraction of patients with persistent MRD at the end of consolidation or for those who relapse. In the pre-ATO era, relapsed patients were usually treated with readministration of ATRA and chemotherapy as salvage therapy, generally containing high-dose cytarabine and an anthracycline, followed by further post-remission chemotherapy and/or HSCT. ATO-based regimens are presently regarded as the first option for relapsed APL. The selection of the most appropriate post-remission treatment option for patients in second CR (CR2), as well as the modality of HSCT when indicated, depends on several variables, such as pre-transplant molecular status, duration of first remission, age, and donor availability. Although with a moderate level of evidence, based on recent retrospective studies, autologous HSCT would be at present the preferred option for consolidation for patients in molecular CR2. Allogeneic HSCT could be considered in patients with a very early relapse or those beyond CR2. Nevertheless, the superiority of HSCT as consolidation over other alternatives without transplantation has recently been questioned in some studies, which justify a prospective controlled study to resolve this still controversial issue.
    Keywords:  acute promyelocytic leukaemia; all-trans retinoic acid (ATRA); arsenic trioxide; hematopoietic (stem) cell transplantation (HCT); relapse
  7. Immunology. 2021 Apr 09.
      The impairment of the cystic fibrosis transmembrane conductance regulator (CFTR) activity induces intracellular chloride (Cl- ) accumulation. The anion Cl- , acting as a second messenger, stimulates the secretion of interleukin-1β (IL-1β), which starts an autocrine positive feedback loop. Here we show that NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (CASP1) are indirectly modulated by the intracellular Cl- concentration, showing maximal expression and activity at 75 mM Cl- , in the presence of the ionophores nigericin and tributyltin. The expression of PYD and CARD domain containing (PYCARD/ASC) remained constant from 0 to 125 mM Cl- . The CASP1 inhibitor VX-765 and the NLRP3 inflammasome inhibitor MCC950 completely blocked the Cl- -stimulated IL-1β mRNA expression and partially the IL-1β secretion. DCF fluorescence (cellular reactive oxygen species, cROS) and MitoSOX fluorescence (mitochondrial ROS, mtROS) also showed maximal ROS levels at 75 mM Cl- , a response strongly inhibited by the ROS scavenger N-acetyl-L-cysteine (NAC) or the NADPH oxidase (NOX) inhibitor GKT137831. These inhibitors also affected CASP1 and NLRP3 mRNA and protein expression. More importantly, the serum/glucocorticoid regulated kinase 1 (SGK1) inhibitor GSK650394, or its shRNAs, completely abrogated the IL-1β mRNA response to Cl- and the IL-1β secretion, interrupting the autocrine IL-1β loop. The results suggest that Cl- effects are mediated by SGK1, which under Cl- modulation stimulates the secretion of mature IL-1β, in turn, responsible for the upregulation of ROS, CASP1, NLRP3, and IL-1β itself, through autocrine signaling.
    Keywords:  CFTR; NLRP3; ROS; SGK1; autocrine signaling; chloride anion; chloride channel; inflammasome; interleukin; second messenger
  8. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021 Apr;29(2): 433-438
      OBJECTIVE: To investigate the significance of low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in the Wnt/β-catenin signaling pathway in the pathogenesis and prognosis of childhood acute lymphoblastic leukemia (ALL).METHODS: A total of 43 children who were newly diagnosed and achieved complete remission after remission induction therapy were enrolled. The children before treatment were included in incipient group, and after treatment when achieved complete remission included in remission group. A total of 39 children with immune thrombocytopenia were enrolled in control group. Three milliliter bone marrow samples were collected from above-mentioned each group. QRT-PCR was used to determine the mRNA expression of LRP5 and LRP6 in blood mononuclear cells of bone marrow. Western blot was used to detect the protein expression of LRP5 and LRP6. According to the protein expression levels of LRP5 and LRP6, the children were divided into low-expression group and high-expression group, and the clinical biological characteristics were compared between these two groups. Survival analysis was performed by Kaplan-Meier method.
    RESULTS: Both mRNA and protein expression levels of LRP5 and 6 were upregulated in the incipient group compared with the control and remission group (P<0.05). The mRNA and protein expressions of LRP5 and LRP6 in the high-risk group were higher than those in the medium-risk group (P<0.05), it is the same as in the medium-risk group than the low-risk group (P<0.05). The mRNA and protein expressions of LRP5 and 6 positively correlated with risk degree in the incipient group (rLRP5 mRNA=0.84, P<0.05; rLRP6 mRNA=0.66, P<0.05; rLRP5 protein=0.82, P<0.05; rLRP6 protein=0.76, P<0.05). The white blood cell count and lactate dehydrogenase in LRP5 and LRP6 high expression group were significantly higher than those in low expression group (P<0.05), while there was no significant difference in other biological characteristics. Kaplan-meier survival analysis showed that in the 43 children 3-year overall survival rate and event-free survival rate was (91.7±4.7)% and (87.6±5.2)%, respectively.
    CONCLUSION: The high expression of LRP5/6 may be one of the pathogenesis of childhood ALL, and the degree of LRP5/6 increase may be related to the risk level.
  9. FASEB J. 2021 May;35(5): e21490
      Endotherms in cold regions improve heat-producing capacity when preparing for winter. We know comparatively little about how this change is fueled by seasonal adaptation in cellular respiration. Thus, we studied the changes of mitochondrial function in red blood cells in sympatric Coal (Periparus ater), Blue (Cyanistes caeruleus), and Great (Parus major) tits between autumn and winter. These species differ more than twofold in body mass and in several aspects of their foraging ecology and social dominance, which could require differential seasonal adaptation of energy expenditure. Coal and Great tits in particular upregulated the mitochondrial respiration rate and mitochondrial volume in winter. This was not directed toward ATP synthesis, instead reflecting increased uncoupling of electron transport from ATP production. Because uncoupling is exothermic, this increased heat-producing capacity at the sub-cellular level in winter. This previously unexplored the route of thermogenesis in birds should be addressed in future work.
    Keywords:  cellular metabolism; erythrocyte; overwintering; oxygen consumption; thermal biology
  10. Front Immunol. 2021 ;12 666703
    Keywords:  chimeric antigen receptor (CAR)-T cell; cytokine release syndrome (CRS); cytokines; immune effector cell associated neurotoxicity syndrome (ICANS); pro-inflammatory mediators
  11. Front Endocrinol (Lausanne). 2021 ;12 627745
      Cancer cells characteristically have a high proliferation rate. Because tumor growth depends on energy-consuming anabolic processes, including biosynthesis of protein, lipid, and nucleotides, many tumor-associated conditions, including intermittent oxygen deficiency due to insufficient vascularization, oxidative stress, and nutrient deprivation, results from fast growth. To cope with these environmental stressors, cancer cells, including cancer stem cells, must adapt their metabolism to maintain cellular homeostasis. It is well- known that cancer stem cells (CSC) reprogram their metabolism to adapt to live in hypoxic niches. They usually change from oxidative phosphorylation to increased aerobic glycolysis even in the presence of oxygen. However, as opposed to most differentiated cancer cells relying on glycolysis, CSCs can be highly glycolytic or oxidative phosphorylation-dependent, displaying high metabolic plasticity. Although the influence of the metabolic and nutrient-sensing pathways on the maintenance of stemness has been recognized, the molecular mechanisms that link these pathways to stemness are not well known. Here in this review, we describe the most relevant signaling pathways involved in nutrient sensing and cancer cell survival. Among them, Adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway, mTOR pathway, and Hexosamine Biosynthetic Pathway (HBP) are critical sensors of cellular energy and nutrient status in cancer cells and interact in complex and dynamic ways.
    Keywords:  adenosine monophosphate-activated protein kinase (AMPK) signaling; cancer stem cells; hexosamine biosynthesis pathway (HBP) pathway; mammalian target of rapamycin (mTOR) signaling; nutrient sensing
  12. Semin Cancer Biol. 2021 Apr 05. pii: S1044-579X(21)00103-6. [Epub ahead of print]
      Antibodies targeting programmed cell death protein 1 (PD-1) or its ligand programmed death-ligand 1 (PD-L1) are profoundly changing the methods to treat cancers with long-term clinical benefits. Unlike conventional methods that directly target tumor cells, PD-L1/PD-1 blockade exerts anti-tumor effects largely through reactivating or normalizing cytotoxic T lymphocyte in the tumor microenvironment to combat cancer cells. However, only a small fraction of cancer patients responds well to PD-L1/PD-1 blockade and clinical outcomes have reached a bottleneck without substantial advances. Therefore, better understanding the molecular mechanisms underlying how PD-L1/PD-1 expression is regulated will provide new insights to improve the efficacy of current anti-PD-L1/PD-1 therapy. Here, we provide an update of current progress of PD-L1 and PD-1 post-translational regulations and highlight the mechanism-based combination therapy strategies for a better treatment of human cancer.
    Keywords:  Acetylation; Glycosylation; Immunotherapy; PD-1; PD-L1; PROTAC; Palmitoylation; Phosphorylation; Posttranslational modification; Ubiquitination
  13. FEBS Lett. 2021 Apr 10.
      Mitochondria play a key role in cellular signalling, metabolism and energetics. Proper architecture and remodelling of the inner mitochondrial membrane are essential for efficient respiration, apoptosis and quality control in the cell. Several protein complexes including mitochondrial contact site and cristae organising system (MICOS), F1 FO -ATP synthase, and Optic Atrophy 1 (OPA1), facilitate formation, maintenance and stability of cristae membranes. MICOS, the F1 FO -ATP synthase, OPA1 and inner membrane phospholipids such as cardiolipin and phosphatidylethanolamine interact with each other to organise the inner membrane ultra-structure and remodel cristae in response to the cell's demands. Functional alterations in these proteins or in the biosynthesis pathway of cardiolipin and phosphatidylethanolamine result in an aberrant inner membrane architecture and impair mitochondrial function. Mitochondrial dysfunction and abnormalities hallmark several human conditions and diseases including neurodegeneration, cardiomyopathies and diabetes mellitus. Yet, they have long been regarded as secondary pathological effects. This review discusses emerging evidence of a direct relationship between protein- and lipid-dependent regulation of the inner mitochondrial membrane morphology and diseases such as fatal encephalopathy, Leigh syndrome, Parkinson's disease, and cancer.
    Keywords:  ATP synthase; MICOS; Mitochondria; Opa1; membrane dynamics; membrane morphology; mitochondrial morphology; mitochondrial ultra-structure
  14. Cell Oncol (Dordr). 2021 Apr 09.
      BACKGROUND: Angiogenesis is a key and early step in tumorigenesis, and is known as a hallmark of solid tumors and a key promoter of tumor recurrence. Unlike normal tissue vessels, the architecture of the tumor vasculature is abnormal, being leaky, tortuous, fragile and blind-ended. Perivascular cells are either detached or absent, causing reduction of vascular integrity, an increase in vessel immaturity, incoherent perfusion, defective functionality and enhanced tumor dissemination and metastasis. The abnormal tumor vasculature along with the defective tumor vessel functionality finally causes bouts of hypoxia and acidity in the tumor microenvironment (TME), further reinvigorating tumor aggression. Interstitial hypertension or high interstitial fluid pressure (IFP) is an outcome of tumor hyper-permeability. High IFP can be a barrier for either effective delivery of anti-cancer drugs toward the TME or accumulation of drugs within the tumor area, thus promoting tumor resistance to therapy. Some tumors do, however, not undergo angiogenesis but instead undergo vessel co-option or vascular mimicry, thereby adding another layer of complexity to cancer development and therapy.CONCLUSIONS: Combination of anti-angiogenesis therapy with chemotherapy and particularly with immune checkpoint inhibitors (ICIs) is a promising strategy for a number of advanced cancers. Among the various approaches for targeting tumor angiogenesis, vascular normalization is considered as the most desired method, which allows effective penetration of chemotherapeutics into the tumor area, thus being an appropriate adjuvant to other cancer modalities.
    Keywords:  Angiogenesis; Bevacizumab; Cancer stem cell (CSC); Chemotherapy; Combination therapy; Endothelial cell (EC); Hypoxia; Normalization; Pazopanib; Pericyte; Programmed death-1 receptor (PD-1); Programmed death-ligand 1 (PD-L1); Sunitinib; Tumor microenvironment (TME); Vascular endothelial growth factor (VEGF); Vascular mimicry; Vessel co‐option
  15. Front Immunol. 2021 ;12 645242
      Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.
    Keywords:  T cell metabolism; adoptive T cell transfer; immune checkpoint therapy; tumor infiltrating lymphocytes; tumor metabolism; tumor microenvironment