bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021‒05‒16
twelve papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

  1. Science. 2021 May 14. 372(6543): 716-721
      Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon's bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.
  2. Adv Exp Med Biol. 2021 ;1269 169-177
      Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary and permanent consequence of dysfunctional mitochondria compensating for a poor ATP yield per mole glucose. Instead, the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic or hypoxic) HIF-1 overexpression, oncogene activation (cMyc, Ras), loss of function of tumor suppressors (mutant p53, mutant PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/c-Myc) or deactivated (AMPK) signaling pathways, components of the tumor microenvironment, and HIF-1 cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include (a) considerably accelerated glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, nonessential amino acids, lipids, and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate which stimulates tumor growth and suppression of antitumor immunity (in addition, lactate can serve as an energy source for normoxic cancer cells, contributes to extracellular acidosis, and thus drives malignant progression and resistances to conventional therapies); (f) maintenance of the cellular redox homeostasis and low ROS formation; and (g) HIF-1 overexpression, mutant p53, and mutant PTEN which inhibit mitochondrial biogenesis and functions, thus negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e., aerobic glycolysis in the presence of oxygen and - in principle - functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and - finally - poor patient outcome.
    Keywords:  ATP generation; Aerobic glycolysis; Biosynthesis of macromolecules; Energy homeostasis; Glycolytic phenotype; Glycolytic switch; Lactate accumulation; Metabolic reprogramming; Oncogenesis; Redox homeostasis; Tumor acidosis; Tumor glucose metabolism; Tumor mitochondria; Warburg effect
  3. Cancer Cell. 2020 12 14. pii: S1535-6108(20)30549-3. [Epub ahead of print]38(6): 776-778
      Venetoclax has changed the clinical outlook for elderly and unfit patients with acute myeloid leukemia, but development of resistance is a challenge. In this issue of Cancer Cell, Bhatt et al. provide a general mechanism for how resistance emerges but also indications for how venetoclax-resistant cases may be treated.
  4. Biochim Biophys Acta Gen Subj. 2021 May 06. pii: S0304-4165(21)00073-8. [Epub ahead of print] 129915
      BACKGROUND: P-glycoprotein (P-gp) is a prevalent resistance mediator and it requires considerable cellular energy to ensure ATP dependent efflux of anticancer drugs. The glycolytic pathway generates the majority of catabolic energy in cancer cells; however, the high rates of P-gp activity places added strain on its inherently limited capacity to generate ATP. This is particularly relevant for compounds such as verapamil that are believed to trap P-gp in a futile transport process that requires continuing ATP consumption. Ultimately, this leads to cell death and the hypersensitivity of resistant cells to verapamil is termed collateral sensitivity.RESULTS: We show that the addition of verapamil to resistant cells produces a prominent reduction in ATP levels that supports the idea of disrupted energy homeostasis. Even in the absence of verapamil, P-gp expressing cells display near maximal rates of glycolysis and oxidative phosphorylation, which prevents an adequate response to the demand for ATP to sustain transport activity. Moreover, the near perpetually maximal rate of oxidative phosphorylation in the presence of verapamil resulted in elevated levels of reactive oxygen species that affect cell survival and underscore collateral sensitivity.
    CONCLUSIONS: Our results demonstrate that the strained metabolic profiles of P-gp expressing resistant cancer cells can be overwhelmed by additional ATP demands.
    GENERAL SIGNIFICANCE: Consequently, collateral sensitising drugs may overcome the resistant phenotype by exploiting, rather than inhibiting, the energy demanding activity of pumps such as P-gp.
    Keywords:  ABC transporter; Cancer; Collateral sensitivity; Metabolism; Multidrug resistance; P-glycoprotein
  5. Leuk Lymphoma. 2021 May 12. 1-7
      We compared the transplant outcomes of adult patients with B-cell acute lymphoblastic leukemia characterized by high hyperdiploidy (HeH; 51-65 chromosomes) (n = 29) and those with a normal karyotype (n = 87) by propensity score-matched analysis. There were no significant differences among groups in 3-year probabilities of overall survival (OS, 63.5% vs. 55.3%, p = .553), cumulative relapse incidence (28.6% vs. 28.7%, p = .982), and non-relapse mortality (10.9% vs. 21.4%, p = .303). Three-year OS was significantly worse in HeH patients with third or later complete remission (CR) or non-CR compared with those in first CR (19.0% vs. 69.9%, p = .010). Frequently gained chromosomes +21 (75.9%), +4 (69.0%), +6 (69.0%), +10 (69.0%), and +1 (69.0%) had no significant prognostic impact on the OS of patients with HeH in multivariate analyses. Patients with HeH who may benefit from allogeneic hematopoietic stem cell transplantation should be further analyzed.
    Keywords:  B-cell acute lymphoblastic leukemia; hematopoietic stem cell transplantation; hyperdiploidy; propensity score
  6. Nat Commun. 2021 May 10. 12(1): 2606
      Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.
  7. Life Sci. 2021 May 08. pii: S0024-3205(21)00583-X. [Epub ahead of print] 119597
      This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes.
    Keywords:  Hypoxia inducible factor; Mitochondria; Oxidative phosphorylation; Pyruvate dehydrogenase; Pyruvate dehydrogenase kinase; Warburg metabolism
  8. Dev Cell. 2021 May 11. pii: S1534-5807(21)00357-9. [Epub ahead of print]
      PI5P4Ks are a class of phosphoinositide kinases that phosphorylate PI-5-P to PI-4,5-P2. Distinct localization of phosphoinositides is fundamental for a multitude of cellular functions. Here, we identify a role for peroxisomal PI-4,5-P2 generated by the PI5P4Ks in maintaining energy balance. We demonstrate that PI-4,5-P2 regulates peroxisomal fatty acid oxidation by mediating trafficking of lipid droplets to peroxisomes, which is essential for sustaining mitochondrial metabolism. Using fluorescent-tagged lipids and metabolite tracing, we show that loss of the PI5P4Ks significantly impairs lipid uptake and β-oxidation in the mitochondria. Further, loss of PI5P4Ks results in dramatic alterations in mitochondrial structural and functional integrity, which under nutrient deprivation is further exacerbated, causing cell death. Notably, inhibition of the PI5P4Ks in cancer cells and mouse tumor models leads to decreased cell viability and tumor growth, respectively. Together, these studies reveal an unexplored role for PI5P4Ks in preserving metabolic homeostasis, which is necessary for tumorigenesis.
    Keywords:  PI-4,5-P(2); PI-5-P; PI5P4Ks; cancer; fatty acid; lipid; lipid droplet; metabolism; mitochondria; peroxisome; phosphoinositide; phosphoinositide kinase; sarcoma; β-oxidation
  9. BMC Med Genomics. 2021 May 13. 14(1): 127
      BACKGROUND: This study aimed to determine and verify the prognostic value and potential functional mechanism of signal recognition particle 14 (SRP14) in acute myeloid leukemia (AML) using a genome-wide expression profile dataset.METHODS: We obtained an AML genome-wide expression profile dataset and clinical prognostic data from The Cancer Genome Atlas (TCGA) and GSE12417 databases, and explored the prognostic value and functional mechanism of SRP14 in AML using survival analysis and various online tools.
    RESULTS: Survival analysis showed that AML patients with high SRP14 expression had poorer overall survival than patients with low SRP14 expression. Time-dependent receiver operating characteristic curves indicated that SRP14 had good accuracy for predicting the prognosis in patients with AML. Genome-wide co-expression analysis suggested that SRP14 may play a role in AML by participating in the regulation of biological processes and signaling pathways, such as cell cycle, cell adhesion, mitogen-activated protein kinase, tumor necrosis factor, T cell receptor, DNA damage response, and nuclear factor-kappa B (NF-κB) signaling. Gene set enrichment analysis indicated that SRP14 was significantly enriched in biological processes and signaling pathways including regulation of hematopoietic progenitor cell differentiation and stem cell differentiation, intrinsic apoptotic signaling pathway by p53 class mediator, interleukin-1, T cell mediated cytotoxicity, and NF-κB-inducing kinase/NF-κB signaling. Using the TCGA AML dataset, we also identified four drugs (phenazone, benzydamine, cinnarizine, antazoline) that may serve as SRP14-targeted drugs in AML.
    CONCLUSION: The current results revealed that high SRP14 expression was significantly related to a poor prognosis and may serve as a prognostic biomarker in patients with AML.
    Keywords:  Acute myeloid leukemia; GSE12417; Prognosis; Signal recognition particle 14; The Cancer Genome Atlas
  10. J Cell Physiol. 2021 May 13.
      Daunorubicin (DNR) is used clinically to treat acute myeloid leukemia (AML), while the signaling pathways associated with its cytotoxicity are not fully elucidated. Thus, we investigated the DNR-induced death pathway in the human AML cell lines U937 and HL-60. DNR-induced apoptosis in U937 cells accompanied by downregulation of MCL1 and BCL2L1, upregulation of Phorbol-12-myristate-13-acetate-induced protein 1 (NOXA), and mitochondrial depolarization. DNR induced NOX4-mediated reactive reactive oxygen species (ROS) production, which in turn inactivated Akt and simultaneously activated p38 mitogen-activated protein kinase (MAPK). Activated p38 MAPK and inactivated Akt coordinately increased GSK3β-mediated cAMP response element-binding protein (CREB) phosphorylation, which promoted NOXA transcription. NOXA upregulation critically increased the proteasomal degradation of MCL1 and BCL2L1. The same pathway was also responsible for the DNR-induced death of HL-60 cells. Restoration of MCL1 or BCL2L1 expression alleviated DNR-induced mitochondrial depolarization and cell death. Furthermore, ABT-199 (a BCL2 inhibitor) synergistically enhanced the cytotoxicity of DNR in AML cell lines. Notably, DNR-induced DNA damage was not related to NOXA-mediated degradation of MCL1 and BCL2L1. Collectively, these results indicate that the upregulation of NOXA expression through the NOX4-ROS-p38 MAPK-GSK3β-CREB axis results in the degradation of MCL1 and BCL2L1 in DNR-treated U937 and HL-60 cells. This signaling pathway may provide insights into the mechanism underlying DNR-triggered apoptosis in AML cells.
    Keywords:  MCL1 and BCL2L1 downregulation; daunorubicin; leukemia; p38 MAPK-GSK3β-CREB axis: NOXA transcription
  11. J Radiat Res. 2021 May 05. 62(Supplement_1): i36-i43
      The health risks associated with low-dose radiation, which are a major concern after the Fukushima Daiichi nuclear power plant accident (the Fukushima accident), have been extensively investigated, and the cancer risks from low-dose radiation exposure (below ~ 100 mSv) are thought to be negligible. According to World Health Organization and the United Nations Scientific Committee on the Effects of Atomic Radiation reports, the level of radiation exposure from the Fukushima accident is limited, estimating no significant increased risk from the accident. Radiation-induced cell injury is mainly caused by oxidative damage to biomolecules, including DNA, lipids and proteins. Radiation stimulates metabolic activation within the mitochondria to provide energy for the DNA damage response. Mitochondrial respiratory chain complexes I and III are the most important intracellular source of reactive oxygen species (ROS) during oxidative phosphorylation in eukaryotic cells. Manganese superoxide dismutase and glutathione are key players in redox control within cells. However, perturbation of the antioxidant response leads to chronic oxidative stress in irradiated cells. Excess ROS of mitochondrial origin is reported in cancer-associated fibroblast and promotes carcinogenesis. The aim of this review paper is to discuss critical roles of mitochondria in radiation-related cancer by introducing our recent studies. In particular, elevated mitochondrial ROS in stromal fibroblasts potentiate transforming growth factor-beta (TGF-β) signaling, which triggers smooth muscle actin (α-SMA) expression to stimulate myofibroblast differentiation. Radiation-induced myofibroblasts promote tumor growth by enhancing angiogenesis. Thus, radiation affects both malignant cancer cells and neighboring stromal cells through secretion of soluble factors.
    Keywords:  cancer; mitochondria; radiation; reactive oxygen species; tumor microenvironment
  12. J Allergy Clin Immunol. 2021 May 06. pii: S0091-6749(21)00555-8. [Epub ahead of print]
      The progression through different steps of T-cell development, activation, and effector function is tightly bound to specific cellular metabolic processes. Previous studies established that T-effector cells have a metabolic bias toward aerobic glycolysis, whereas naive and regulatory T cells mainly rely on oxidative phosphorylation. More recently, the field of immunometabolism has drifted away from the notion that mitochondrial metabolism holds little importance in T-cell activation and function. Of note, T cells possess metabolic promiscuity, which allows them to adapt their nutritional requirements according to the tissue environment. Altogether, the integration of these metabolic pathways culminates in the generation of not only energy but also intermediates, which can regulate epigenetic programs, leading to changes in T-cell fate. In this review, we discuss the recent literature on how glycolysis, amino acid catabolism, and fatty acid oxidation work together with the tricarboxylic acid cycle in the mitochondrion. We also emphasize the importance of the electron transport chain for T-cell immunity. We also discuss novel findings highlighting the role of key enzymes, accessory pathways, and posttranslational protein modifications that distinctively regulate T-cell function and might represent prominent candidates for therapeutic purposes.
    Keywords:  CD4; T cell; antibiotics; arginine; fatty acid oxidation; immunometabolism; metabolism; mitochondria; polyamine