bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022‒05‒15
ten papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. The Social Norm of Hematopoietic Stem Cells and Dysregulation in Leukemia.
  2. Hexokinase 3 enhances myeloid cell survival via non-glycolytic functions.
  3. A pan-cancer metabolic atlas of the tumor microenvironment.
  4. Synergistic Effects of Anti-Cancer Drug Administration on Acute Myeloid Leukemia.
  5. Immune-Based Therapeutic Interventions for Acute Myeloid Leukemia.
  6. Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.
  7. Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia.
  8. Tumour driver mutations compromise between cancer growth and immune responses.
  9. Hungry Hematopoietic Stem Cells during Bacterial Infection: Fatty Acid for Food.
  10. Metabolic oscillations during cell-cycle progression.
  1. Int J Mol Sci. 2022 May 03. pii: 5063. [Epub ahead of print]23(9):
    The Social Norm of Hematopoietic Stem Cells and Dysregulation in Leukemia.
    Geoffrey Brown.
      The hematopoietic cell system is a complex ecosystem that meets the steady-state and emergency needs of the production of the mature blood cell types. Steady-state hematopoiesis replaces worn out cells, and the hematopoietic system is highly adaptive to needs during, for example, an infection or bleeding. Hematopoiesis is highly integrated and the cell hierarchy behaves in a highly social manner. The social tailoring of hematopoietic stem cells to needs includes the generation of cells that are biased towards a cell lineage; these cells remain versatile and can still adopt a different pathway having made a lineage "choice", and some cytokines instruct the lineage fate of hematopoietic stem and progenitor cells. Leukemia stem cells, which may well often arise from the transformation of a hematopoietic stem cell, sustain the hierarchy of cells for leukemia. Unlike hematopoietic stem cells, the offspring of leukemia stem cells belongs to just one cell lineage. The human leukemias are classified by virtue of their differentiating or partially differentiating cells belonging to just one cell lineage. Some oncogenes set the fate of leukemia stem cells to a single lineage. Therefore, lineage restriction may be largely an attribute whereby leukemia stem cells escape from the normal cellular society. Additional antisocial behaviors are that leukemia cells destroy and alter bone marrow stromal niches, and they can create their own niches.
    Keywords:  hematopoietic stem cells; leukemia; leukemia stem cells; lineage fate; oncogenes
    DOI:  https://doi.org/10.3390/ijms23095063
  2. Cell Death Dis. 2022 May 11. 13(5): 448
    Hexokinase 3 enhances myeloid cell survival via non-glycolytic functions.
    Kristina Seiler, Magali Humbert, Petra Minder, Iris Mashimo, Anna M Schläfli, Deborah Krauer, Elena A Federzoni, Bich Vu, James J Moresco, John R Yates, Martin C Sadowski, Ramin Radpour, Thomas Kaufmann, Jean-Emmanuel Sarry, Joern Dengjel, Mario P Tschan, Bruce E Torbett.
      The family of hexokinases (HKs) catalyzes the first step of glycolysis, the ATP-dependent phosphorylation of glucose to glucose-6-phosphate. While HK1 and HK2 are ubiquitously expressed, the less well-studied HK3 is primarily expressed in hematopoietic cells and tissues and is highly upregulated during terminal differentiation of some acute myeloid leukemia (AML) cell line models. Here we show that expression of HK3 is predominantly originating from myeloid cells and that the upregulation of this glycolytic enzyme is not restricted to differentiation of leukemic cells but also occurs during ex vivo myeloid differentiation of healthy CD34+ hematopoietic stem and progenitor cells. Within the hematopoietic system, we show that HK3 is predominantly expressed in cells of myeloid origin. CRISPR/Cas9 mediated gene disruption revealed that loss of HK3 has no effect on glycolytic activity in AML cell lines while knocking out HK2 significantly reduced basal glycolysis and glycolytic capacity. Instead, loss of HK3 but not HK2 led to increased sensitivity to ATRA-induced cell death in AML cell lines. We found that HK3 knockout (HK3-null) AML cells showed an accumulation of reactive oxygen species (ROS) as well as DNA damage during ATRA-induced differentiation. RNA sequencing analysis confirmed pathway enrichment for programmed cell death, oxidative stress, and DNA damage response in HK3-null AML cells. These signatures were confirmed in ATAC sequencing, showing that loss of HK3 leads to changes in chromatin configuration and increases the accessibility of genes involved in apoptosis and stress response. Through isoform-specific pulldowns, we furthermore identified a direct interaction between HK3 and the proapoptotic BCL-2 family member BIM, which has previously been shown to shorten myeloid life span. Our findings provide evidence that HK3 is dispensable for glycolytic activity in AML cells while promoting cell survival, possibly through direct interaction with the BH3-only protein BIM during ATRA-induced neutrophil differentiation.
    DOI:  https://doi.org/10.1038/s41419-022-04891-w
  3. Cell Rep. 2022 May 10. pii: S2211-1247(22)00567-8. [Epub ahead of print]39(6): 110800
    A pan-cancer metabolic atlas of the tumor microenvironment.
    Neha Rohatgi, Umesh Ghoshdastider, Probhonjon Baruah, Tanmay Kulshrestha, Anders Jacobsen Skanderup.
      Tumors are heterogeneous cellular environments with entwined metabolic dependencies. Here, we use a tumor transcriptome deconvolution approach to profile the metabolic states of cancer and non-cancer (stromal) cells in bulk tumors of 20 solid tumor types. We identify metabolic genes and processes recurrently altered in cancer cells across tumor types, highlighting pan-cancer upregulation of deoxythymidine triphosphate (dTTP) production. In contrast, the tryptophan catabolism rate-limiting enzymes IDO1 and TDO2 are highly overexpressed in stroma, raising the hypothesis that kynurenine-mediated suppression of antitumor immunity may be predominantly constrained by the stroma. Oxidative phosphorylation is the most upregulated metabolic process in cancer cells compared to both stromal cells and a large atlas of cancer cell lines, suggesting that the Warburg effect may be less pronounced in cancer cells in vivo. Overall, our analysis highlights fundamental differences in metabolic states of cancer and stromal cells inside tumors and establishes a pan-cancer resource to interrogate tumor metabolism.
    Keywords:  CP: Cancer; CP: Metabolism; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2022.110800
  4. FASEB J. 2022 May;36 Suppl 1
    Synergistic Effects of Anti-Cancer Drug Administration on Acute Myeloid Leukemia.
    Margaret A Canavan.
      Acute Myeloid Leukemia (AML) is a malignant disease where there is a high rate of chemoresistance, or drug resistance, in patients which is a leading cause of treatment failure. Current clinical treatments of AML include Cabazitaxel and Gemcidibine, which affect DNA replication in two different ways. A potential strategy to overcome chemoresistance is to treat resistant-AML cells with combinations of drugs that have different therapeutic targets. Since BCL-2 proteins, which control apoptosis, are often upregulated in AML, we hypothesize that BCL-2 inhibitors such as Venetoclax are candidate drugs to be considered for use in treating Cabazitaxel-resistant and/or Gemcitdibine-resistant AML. Moreover, cancer cells are also known to have dependence on glucose metabolism and therefore glucose inhibitors, such as WZB117, are also candidate drugs to overcome chemoresistance in AML. Therefore, the overarching goal of this project is to investigate the potential synergetic effects of a WZB117 and Venetoclax on chemo-resistant AML cells Using the AML cell line HL60, baseline sensitivity to Cabazitaxel and Gemcidibine have been determined using GI50 assays. The GI50 values obtained were 1.35uM for Cabazitaxel and 0.94uM for Gemcidibine. Currently, resistant cells are being developed by treating HL60 cells with the GI10 values for each drug until their normal growth rate returns, at which time new GI50 values will be obtained and the resistant cells dosed again to perpetuate resistance. Baseline sensitivity of HL60 cells to WZB117 and Venetoclax is also ongoing. Once cells reach 5-fold resistance for each drug, the effectiveness of WZB117 alone, Venetoclax alone, and both drugs in combination will be assessed to determine if these drugs are a viable option for inducing apoptosis in Cabazitaxel-resistant and/or Gemcitabine-resistant AML cells.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R6201
  5. Cancer Treat Res. 2022 ;183 225-254
    Immune-Based Therapeutic Interventions for Acute Myeloid Leukemia.
    Fabiana Perna, Manuel R Espinoza-Gutarra, Giuseppe Bombaci, Sherif S Farag, Jennifer E Schwartz.
      Acute myeloid leukemia (AML) is an aggressive, clonally heterogeneous, myeloid malignancy, with a 5-year overall survival of approximately 27%. It constitutes the most common acute leukemia in adults, with an incidence of 3-5 cases per 100,000 in the United States. Despite great advances in understanding the molecular mechanisms underpinning leukemogenesis, the past several decades had seen little change to the backbone of therapy, comprised of an anthracycline-based induction regimen for those who are fit enough to receive it, followed by risk-stratified post-remission therapy with consolidation cytarabine or allogeneic stem cell transplantation (allo-SCT). Allo-SCT is the most fundamental form of immunotherapy in which donor cytotoxic T and NK cells recognize and eradicate residual AML in the graft-versus-leukemia (GvL) effect. Building on that, several alternative or synergistic approaches to exploit both self and foreign immunity against AML have been developed. Checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors block proteins found on T cells or cancer cells that stop the immune system from attacking the cancer cells. They have been used with limited success in both the AML relapsed/refractory (R/R) and post SCT settings. AML tumor mutational burden is low compared to solid tumors and thus, it is less likely to generate neoantigens and respond to antibody-mediated checkpoint blockade that has shown unprecedented results in solid tumors. Therefore, alternative therapeutic strategies that work independently of the T cell receptor (TCR) specificity have been developed. They include bispecific antibodies, which recruit T cells through CD3 engagement, and in AML have shown an overall response rate ranging between 14 and 30% in early phase trials. Chimeric Antigen Receptor (CAR) T cell therapy is a type of treatment in which T cells are genetically engineered to produce a recombinant receptor that redirects the specificity and function of T lymphocytes. However, lack of cell surface targets exclusively expressed on AML cells including Leukemic Stem Cells (LSCs) combined with clonal heterogeneity represents the biggest challenge in developing CAR therapy for AML. Antibody-Drug Conjugates (ADC) constitute the only FDA-approved immunotherapy to treat AML with Gemtuzumab Ozogamicin, a CD33-specific ADC used in CEBPα-mutated AML. The identification of additional cell surface targets is critical for the development of other ADC's potentially useful in the induction and maintenance regimens, given the ease at which these reagents can be generated and managed. Here, we will review those immune-based therapeutic interventions and highlight active areas of research investigations toward fulfillment of the great promise of immunotherapy to AML.
    DOI:  https://doi.org/10.1007/978-3-030-96376-7_8
  6. Nat Commun. 2022 May 12. 13(1): 2614
    Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.
    Mahmoud A Bassal, Saumya E Samaraweera, Kelly Lim, Brooks A Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A Casolari, Diana G Iarossi, Ilaria S Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D Lewis, Anna L Brown, Daniel G Tenen, Nirmal Robinson, David M Ross, Ravindra Majeti, Thomas J Gonda, Daniel Thomas, Richard J D'Andrea.
      The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.
    DOI:  https://doi.org/10.1038/s41467-022-30223-9
  7. Front Oncol. 2022 ;12 867684
    Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia.
    Azza M Kamel, Nahla M Elsharkawy, Eman Z Kandeel, Marwa Hanafi, Mohammed Samra, Randa A Osman.
      Acute myeloid leukemia (AML) is a heterogenous disease in which the initiation and maintenance of the malignant clone is blamed on a rare population of leukemia stem cells (LSCs). The persistence of such a malignant population is referred to as measurable/minimal residual disease (MRD). Evaluation of MRD is the gold standard for follow-up of therapy and constitutes an independent prognostic parameter. As LSCs are the main contributor to the persistence of MRD, then MRD should correlate with the bulk of LSCs at the individual case level. MRD is measured at defined time points during therapy. However, LSCs can be evaluated at diagnosis, which ensures the advantage of early prediction of high-risk patients and allows for early therapeutic decisions. Using two simple four-color monoclonal antibody combinations (CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33) and the prism function of the Coulter Navios flow cytometer, the frequency of LSC subsets was evaluated in 84 newly diagnosed adult AML patients. For each panel, 16 possible combinations were detected. Our results showed that there was extreme variability in the percentage of the LSC fraction between different cases, as well as at the individual case level. For each LSC subset, the median value was used to divide cases into low and high expressors. LSC subsets that showed an impact on overall survival (OS) and disease-free survival (DFS) included CD123+, CD 123+/CD34-, CD34-/CD38+/CD123+, CD34+/CD38-/CD123+, CD133+, and CD133+/CD33-. On multivariate analysis, only CD123 (p ≤ 0.001, SE = 0.266, HR = 2.8, 95% CI = 1.74.7) and CD133+/CD33- (p = 0.017, SE = 0.263, HR = 1.9, 95% CI = 1.1-3.1) retained their significance for OS. Likewise, only CD34+/CD38-/CD123+ (p ≤ 0.001, HR 2.3, SE: 0.499, 95% CI: 2.4-17.4) and CD133 (p = 0.015, HR 2.3, SE 0.34, 95% CI: 1.2-4.4) retained their statistical significance for DFS. The LSC frequency at diagnosis showed a moderate to strong correlation with MRD status at day 14 and day 28. In conclusion, the level of LSCs at diagnosis correlated with MRD status at day 14 and day 28 in AML patients and had a deleterious impact on OS and DFS. It may be used as an early marker for high-risk patients allowing for early therapeutic decisions.
    Keywords:  AML; CD123; CD133; LSC; MRD
    DOI:  https://doi.org/10.3389/fonc.2022.867684
  8. Nature. 2022 May 11.
    Tumour driver mutations compromise between cancer growth and immune responses.
      
    Keywords:  Cancer; Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-022-01138-8
  9. Immunometabolism. 2022 ;pii: e220011. [Epub ahead of print]4(2):
    Hungry Hematopoietic Stem Cells during Bacterial Infection: Fatty Acid for Food.
    Marie-Dominique Filippi.
      Hematopoietic stem cells (HSC) directly initiate a response to bacterial infections by rapidly entering the cell cycle in order to produce mature blood cells. An important issue in the field of HSC biology is to understand how metabolic activities of HSC are fueled during specific condition that require HSC activation. In their paper, Mistry et al. provide evidence that bacterial infections trigger an increased in free fatty acid uptake by HSC that fuel fatty acid oxidation and mitochondrial respiration activities. This increased fatty acid uptake is exclusively dependent on the upregulation of the fatty acid transporter CD36. This study shed important light into the metabolic needs of HSC during septic conditions.
    Keywords:  CD36; fatty acid; hematopoietic stem cells; infection; mitochondria
    DOI:  https://doi.org/10.20900/immunometab20220011
  10. Trends Endocrinol Metab. 2022 May 06. pii: S1043-2760(22)00063-7. [Epub ahead of print]
    Metabolic oscillations during cell-cycle progression.
    Philippe Icard, Luca Simula.
      We discuss how metabolism changes during different phases of the cell cycle to sustain biosynthesis and replication in normal and cancer cells. We also highlight how several master regulators of cell cycle, such as cyclin-cyclin-dependent kinases (cyc-CDK complexes) and E3 proteasome ligases, modulate key metabolic enzymes to support cell-cycle progression.
    Keywords:  Warburg effect; cancer; cell cycle; cell metabolism
    DOI:  https://doi.org/10.1016/j.tem.2022.04.006
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