bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–02–05
seven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Leukemic stem cells and therapy resistance in acute myeloid leukemia.
  2. Human ILC1s target leukemia stem cells and control development of AML.
  3. Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells.
  4. Resistance Mechanism of Acute Myeloid Leukemia Cells Against Daunorubicin and Cytarabine: A Literature Review.
  5. Mitochondrial metabolism: a predictive biomarker of radiotherapy efficacy and toxicity.
  6. The clinical impact of the molecular landscape of acute myeloid leukemia.
  7. Tumor lactic acid: a potential target for cancer therapy.
  1. Haematologica. 2023 02 01. 108(2): 353-366
    Leukemic stem cells and therapy resistance in acute myeloid leukemia.
    Patrick Stelmach, Andreas Trumpp.
      A major obstacle in the treatment of acute myeloid leukemia (AML) is refractory disease or relapse after achieving remission. The latter arises from a few therapy-resistant cells within minimal residual disease (MRD). Resistant cells with long-term self-renewal capacity that drive clonal outgrowth are referred to as leukemic stem cells (LSC). The cancer stem cell concept considers LSC as relapse-initiating cells residing at the top of each genetically defined AML subclone forming epigenetically controlled downstream hierarchies. LSC display significant phenotypic and epigenetic plasticity, particularly in response to therapy stress, which results in various mechanisms mediating treatment resistance. Given the inherent chemotherapy resistance of LSC, targeted strategies must be incorporated into first-line regimens to prevent LSC-mediated AML relapse. The combination of venetoclax and azacitidine is a promising current strategy for the treatment of AML LSC. Nevertheless, the selection of patients who would benefit either from standard chemotherapy or venetoclax + azacitidine treatment in first-line therapy has yet to be established and the mechanisms of resistance still need to be discovered and overcome. Clinical trials are currently underway that investigate LSC susceptibility to first-line therapies. The era of single-cell multi-omics has begun to uncover the complex clonal and cellular architectures and associated biological networks. This should lead to a better understanding of the highly heterogeneous AML at the inter- and intra-patient level and identify resistance mechanisms by longitudinal analysis of patients' samples. This review discusses LSC biology and associated resistance mechanisms, potential therapeutic LSC vulnerabilities and current clinical trial activities.
    DOI:  https://doi.org/10.3324/haematol.2022.280800
  2. Res Sq. 2023 Jan 10. pii: rs.3.rs-2319959. [Epub ahead of print]
    Human ILC1s target leukemia stem cells and control development of AML.
    Michael Caligiuri, Zhenlong Li, Rui Ma, Hejun Tang, Jianying Zhang, Guido Marcucci, Jianhua Yu.
      Innate lymphocytes can mediate cancer immunosurveillance and protect against disease. We have demonstrated that mouse type I innate lymphoid cells (ILC1s) can contribute to controlling the growth of acute myeloid leukemia (AML). However, the functional roles of human ILC1s in AML remain largely undefined. Here, we found that the ILC1s in patients with AML are impaired while a high expression of the ILC1 gene signature is associated with better overall survival in AML. By directly interacting with leukemia stem cells (LSCs), human ILC1s can eliminate LSCs via production of IFNγ and block LSC differentiation into M2 macrophage-like, leukemia-supporting cells through TNF. Collectively, these effects converge to limit leukemogenesis in vivo . We also identified Lin - CD127 + CD161 - CRTH2 - CD117 - cells as the human ILC1 subset. The use of umbilical cord blood (UCB) CD34 + hematopoietic stem cells to generate CD161 - ILC1s could allow for a readily available supply of ILC1s to be produced for human adoptive transfer studies. Together, our findings provide evidence that targeting human ILC1s may be a promising therapeutic approach for prolongation of disease-free survival in AML.
    DOI:  https://doi.org/10.21203/rs.3.rs-2319959/v1
  3. Eur J Med Chem. 2023 Jan 21. pii: S0223-5234(23)00055-7. [Epub ahead of print]249 115140
    Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells.
    Yulin Liu, Yujiao Wei, Xuan Wang, Lan Ma, Xuechun Li, Yue Sun, Yanjie Wu, Li Zhang, Jiefu Wang, Ming Li, Kun Zhang, Mingming Wei, Guang Yang, Cheng Yang.
      Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.
    Keywords:  Acute myeloid leukemia; Cell differentiation; HDACs/CDKs dual inhibitors; Leukemic stem cells; Molecular hybridization
    DOI:  https://doi.org/10.1016/j.ejmech.2023.115140
  4. Cureus. 2022 Dec;14(12): e33165
    Resistance Mechanism of Acute Myeloid Leukemia Cells Against Daunorubicin and Cytarabine: A Literature Review.
    Elly Y Arwanih, Melva Louisa, Ikhwan Rinaldi, Septelia I Wanandi.
      Acute myeloid leukemia (AML) is a hematological malignancy commonly found in adult patients. Low overall survival and resistance to therapy are the main issues in AML. The first line of treatment for AML chemotherapy is the induction phase, namely, the phase to induce remission by administering a combination of daunorubicin (DNR) for three days followed by administration of cytarabine (Ara-C) with continuous infusion for seven days, which is referred to as "3 + 7." Such induction therapy has been the standard therapy for AML for the last four decades. This review article is made to discuss daunorubicin and cytarabine from their chemical structure, pharmacodynamics, pharmacokinetics, and mechanisms of resistance in AML.
    Keywords:  acute myeloid leukemia; aml; chemotherapy; cytarabine; daunorubicin; leukemia; resistance; treatment
    DOI:  https://doi.org/10.7759/cureus.33165
  5. J Cancer Res Clin Oncol. 2023 Jan 31.
    Mitochondrial metabolism: a predictive biomarker of radiotherapy efficacy and toxicity.
    Farzad Taghizadeh-Hesary, Mohammad Houshyari, Mohammad Farhadi.
       INTRODUCTION: Radiotherapy is a mainstay of cancer treatment. Clinical studies revealed a heterogenous response to radiotherapy, from a complete response to even disease progression. To that end, finding the relative prognostic factors of disease outcomes and predictive factors of treatment efficacy and toxicity is essential. It has been demonstrated that radiation response depends on DNA damage response, cell cycle phase, oxygen concentration, and growth rate. Emerging evidence suggests that altered mitochondrial metabolism is associated with radioresistance.
    METHODS: This article provides a comprehensive evaluation of the role of mitochondria in radiotherapy efficacy and toxicity. In addition, it demonstrates how mitochondria might be involved in the famous 6Rs of radiobiology.
    RESULTS: In terms of this idea, decreasing the mitochondrial metabolism of cancer cells may increase radiation response, and enhancing the mitochondrial metabolism of normal cells may reduce radiation toxicity. Enhancing the normal cells (including immune cells) mitochondrial metabolism can potentially improve the tumor response by enhancing immune reactivation. Future studies are invited to examine the impacts of mitochondrial metabolism on radiation efficacy and toxicity. Improving radiotherapy response with diminishing cancer cells' mitochondrial metabolism, and reducing radiotherapy toxicity with enhancing normal cells' mitochondrial metabolism.
    Keywords:  Mitochondria; Personalized oncology; Radiosensitivity; Radiotherapy
    DOI:  https://doi.org/10.1007/s00432-023-04592-7
  6. Haematologica. 2023 02 01. 108(2): 308-320
    The clinical impact of the molecular landscape of acute myeloid leukemia.
    Sabine Kayser, Mark J Levis.
      Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk-stratification schemes and have been proven to be clinically relevant, targetable lesions. The current World Health Organization Classification of myeloid neoplasms and leukemia includes eight AML categories defined by recurrent genetic abnormalities as well as three categories defined by gene mutations. We here discuss the utility of molecular markers in AML in prognostication and treatment decision-making. New therapies based on targetable markers include IDH inhibitors (ivosidenib, enasidenib), venetoclax-based therapy, FLT3 inhibitors (midostaurin, gilteritinib, and quizartinib), gemtuzumab ozogamicin, magrolimab and menin inhibitors.
    DOI:  https://doi.org/10.3324/haematol.2022.280801
  7. Arch Pharm Res. 2023 Feb 02.
    Tumor lactic acid: a potential target for cancer therapy.
    Jun-Kyu Byun.
      Tumor development is influenced by circulating metabolites and most tumors are exposed to substantially elevated levels of lactic acid and low levels of nutrients, such as glucose and glutamine. Tumor-derived lactic acid, the major circulating carbon metabolite, regulates energy metabolism and cancer cell signaling pathways, while also acting as an energy source and signaling molecule. Recent studies have yielded new insights into the pro-tumorigenic action of lactic acid and its metabolism. These insights suggest an anti-tumor therapeutic strategy targeting the oncometabolite lactic acid, with the aim of improving the efficacy and clinical safety of tumor metabolism inhibitors. This review describes the current understanding of the multifunctional roles of tumor lactic acid, as well as therapeutic approaches targeting lactic acid metabolism, including lactate dehydrogenase and monocarboxylate transporters, for anti-cancer therapy.
    Keywords:  Anti-tumor therapy; Lactate dehydrogenases; Lactic acid; Lactic acid blocking strategy; Monocarboxylate transporters; Tumors
    DOI:  https://doi.org/10.1007/s12272-023-01431-8
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