bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022‒02‒20
nine papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia.
  2. Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.
  3. A "Weird" Mitochondrial Fatty Acid Oxidation as a Metabolic "Secret" of Cancer.
  4. Targeting cancer stem cells with antibiotics inducing mitochondrial dysfunction as an alternative anticancer therapy.
  5. Metabolic determination of cell fate through selective inheritance of mitochondria.
  6. Bedside to Bench and Back: Identifying a New Clinically Relevant Driver in Pediatric Acute Myeloid Leukemia.
  7. NOX2: determinant of acute myeloid leukemia survival.
  8. Molecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment.
  9. Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML.
  1. Cancers (Basel). 2022 Jan 19. pii: 486. [Epub ahead of print]14(3):
    High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia.
    Longlong Liu, Pradeep Kumar Patnana, Xiaoqing Xie, Daria Frank, Subbaiah Chary Nimmagadda, Annegret Rosemann, Marie Liebmann, Luisa Klotz, Bertram Opalka, Cyrus Khandanpour.
      Acute myeloid leukemia (AML) is a group of hematological cancers with metabolic heterogeneity. Oxidative phosphorylation (OXPHOS) has been reported to play an important role in the function of leukemic stem cells and chemotherapy-resistant cells and are associated with inferior prognosis in AML patients. However, the relationship between metabolic phenotype and genetic mutations are yet to be explored. In the present study, we demonstrate that AML cell lines have high metabolic heterogeneity, and AML cells with MLL/AF9 have upregulated mitochondrial activity and mainly depend on OXPHOS for energy production. Furthermore, we show that metformin repressed the proliferation of MLL/AF9 AML cells by inhibiting mitochondrial respiration. Together, this study demonstrates that AML cells with an MLL/AF9 genotype have a high dependency on OXPHOS and could be therapeutically targeted by metformin.
    Keywords:  MLL/AF9; OXPHOS; heterogeneity; metformin
    DOI:  https://doi.org/10.3390/cancers14030486
  2. Cancers (Basel). 2022 Jan 22. pii: 553. [Epub ahead of print]14(3):
    Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.
    Anna Halama, Karsten Suhre.
      Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.
    Keywords:  cancer; cancer treatment; drug resistance; glutamine metabolism; glutaminolysis inhibition; metabolism
    DOI:  https://doi.org/10.3390/cancers14030553
  3. Oxid Med Cell Longev. 2022 ;2022 2339584
    A "Weird" Mitochondrial Fatty Acid Oxidation as a Metabolic "Secret" of Cancer.
    Zhivko Zhelev, Ichio Aoki, Dessislava Lazarova, Tatyana Vlaykova, Tatsuya Higashi, Rumiana Bakalova.
      Cancer metabolism is an extensively studied field since the discovery of the Warburg effect about 100 years ago and continues to be increasingly intriguing and enigmatic so far. It has become clear that glycolysis is not the only abnormally activated metabolic pathway in the cancer cells, but the same is true for the fatty acid synthesis (FAS) and mevalonate pathway. In the last decade, a lot of data have been accumulated on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. In this article, we discuss how mFAO can escape normal regulation under certain conditions and be overactivated. Such abnormal activation of mitochondrial β-oxidation can also be combined with mutations in certain enzymes of the Krebs cycle that are common in cancer. If overactivated β-oxidation is combined with other common cancer conditions, such as dysfunctions in the electron transport complexes, and/or hypoxia, this may alter the redox state of the mitochondrial matrix. We propose the idea that the altered mitochondrial redox state and/or inhibited Krebs cycle at certain segments may link mitochondrial β-oxidation to the citrate-malate shuttle instead to the Krebs cycle. We call this abnormal metabolic condition "β-oxidation shuttle". It is unconventional mFAO, a separate metabolic pathway, unexplored so far as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and ultimately a source of proliferation. It is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathway.
    DOI:  https://doi.org/10.1155/2022/2339584
  4. Biochem Pharmacol. 2022 Feb 15. pii: S0006-2952(22)00060-0. [Epub ahead of print] 114966
    Targeting cancer stem cells with antibiotics inducing mitochondrial dysfunction as an alternative anticancer therapy.
    Igor Karp, Alex Lyakhovich.
      Traditional cancer treatments based on chemo- and/or radiotherapy effectively kill only differentiated cancer cells, while metastasis and recurrences are caused by surviving cancer resistant cells (CRC) or a special subpopulation of cancer cells known as cancer stem cells (CSC). Both of these cell types compromise anticancer treatment through various mechanisms, including withdrawal of the anticancer drug through ATP-binding cassette transporters, increased expression of DNA repair genes, or transition to a quiescent phenotype. In contrast to many cancers, where energy consumption is due to glycolysis (Warburg effect), the bioenergetics of CSC and CRC is most often related to oxidative phosphorylation, that is, dependent on mitochondrial function. Therefore, compounds that induce mitochondrial dysfunction (MDF), such as some antibiotics, may represent an alternative approach to anticancer therapy. This review summarizes the major recent works on the use of antibiotics to target tumors via CSC and suggests next steps for developing this approach.
    Keywords:  OXPHOS; antibiotics; anticancer therapy; cancer resistance; cancer stem cells; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.bcp.2022.114966
  5. Nat Cell Biol. 2022 Feb;24(2): 148-154
    Metabolic determination of cell fate through selective inheritance of mitochondria.
    Julia Döhla, Emilia Kuuluvainen, Nadja Gebert, Ana Amaral, Johanna I Englund, Swetha Gopalakrishnan, Svetlana Konovalova, Anni I Nieminen, Ella S Salminen, Rubén Torregrosa Muñumer, Kati Ahlqvist, Yang Yang, Hien Bui, Timo Otonkoski, Reijo Käkelä, Ville Hietakangas, Henna Tyynismaa, Alessandro Ori, Pekka Katajisto.
      Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions1-4. How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron-sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria.
    DOI:  https://doi.org/10.1038/s41556-021-00837-0
  6. Blood Cancer Discov. 2022 Feb 16. pii: bloodcandisc.0004.2022. [Epub ahead of print]
    Bedside to Bench and Back: Identifying a New Clinically Relevant Driver in Pediatric Acute Myeloid Leukemia.
    Robert P Hasserjian, Valentina Nardi.
      In this issue of Blood Cancer Discovery, Dr Masayuki Umeda and colleagues identify and comprehensively analyze a novel recurrent UBTF mutation (tandem duplications) in pediatric acute myeloid leukemia. Acute myeloid leukemia cases with UBTF tandem duplications display distinctive biologic features, including association with FLT3-ITD and WT1 mutations and high-risk disease, and appear to represent a new genetic subtype of acute myeloid leukemia.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-22-0004
  7. Haematologica. 2022 Feb 17.
    NOX2: determinant of acute myeloid leukemia survival.
    Courtney L Jones.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.280677
  8. Cancers (Basel). 2022 Feb 01. pii: 756. [Epub ahead of print]14(3):
    Molecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment.
    V A Shiva Ayyadurai, Prabhakar Deonikar, Kevin G McLure, Kathleen M Sakamoto.
      A molecular systems architecture is presented for acute myeloid leukemia (AML) to provide a framework for organizing the complexity of biomolecular interactions. AML is a multifactorial disease resulting from impaired differentiation and increased proliferation of hematopoietic precursor cells involving genetic mutations, signaling pathways related to the cancer cell genetics, and molecular interactions between the cancer cell and the tumor microenvironment, including endothelial cells, fibroblasts, myeloid-derived suppressor cells, bone marrow stromal cells, and immune cells (e.g., T-regs, T-helper 1 cells, T-helper 17 cells, T-effector cells, natural killer cells, and dendritic cells). This molecular systems architecture provides a layered understanding of intra- and inter-cellular interactions in the AML cancer cell and the cells in the stromal microenvironment. The molecular systems architecture may be utilized for target identification and the discovery of single and combination therapeutics and strategies to treat AML.
    Keywords:  CytoSolve; acute myeloid leukemia (AML); immune cells; leukemia stem cells (LSC); molecular systems architecture; systems biology; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers14030756
  9. Leukemia. 2022 Feb 17.
    Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML.
    Mika Caplan, Karli J Wittorf, Kasidy K Weber, Samantha A Swenson, Tyler J Gilbreath, R Willow Hynes-Smith, Catalina Amador, R Katherine Hyde, Shannon M Buckley.
      Acute myeloid leukemia (AML) is a devastating cancer affecting the hematopoietic system. Previous research has relied on RNA sequencing and microarray techniques to study the downstream effects of genomic alterations. While these studies have proven efficacious, they fail to capture the changes that occur at the proteomic level. To interrogate the effect of protein expression alterations in AML, we performed a quantitative mass spectrometry in parallel with RNAseq analysis using AML mouse models. These combined results identified 34 proteins whose expression was upregulated in AML tumors, but strikingly, were unaltered at the transcriptional level. Here we focus on mitochondrial electron transfer proteins ETFA and ETFB. Silencing of ETFA and ETFB led to increased mitochondrial activity, mitochondrial stress, and apoptosis in AML cells, but had little to no effect on normal human CD34+ cells. These studies identify a set of proteins that have not previously been associated with leukemia and may ultimately serve as potential targets for therapeutic manipulation to hinder AML progression and help contribute to our understanding of the disease.
    DOI:  https://doi.org/10.1038/s41375-022-01518-z
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