bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–01–29
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells.
  2. When cancer drug resistance meets metabolomics (bulk, single-cell and/or spatial): Progress, potential, and perspective.
  3. A census of complexes formed by mitochondrial proteins.
  4. The promise of targeting heme and mitochondrial respiration in normalizing tumor microenvironment and potentiating immunotherapy.
  5. Cancer Stem Cells and Their Therapeutic Usage.
  6. Editorial: Developing combined modality therapy with mitochondria-targeting strategy.
  7. The role of cancer cell bioenergetics in dormancy and drug resistance.
  8. Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress.
  9. Mitochondrial PD-L1 modulates cancer immunotherapy.
  10. AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.
  11. To be or not to be a fat burner, that is the question for cpt1c in cancer cells.
  1. Blood Adv. 2023 Jan 27. pii: bloodadvances.2022008787. [Epub ahead of print]
    Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells.
    Feng Pan, Masayuki Iwasaki, Wenqi Wu, Yanan Jiang, Xin Yang, Li Zhu, Zhigang Zhao, Michael L Cleary.
      Acute myeloid leukemia (AML) with MLL gene rearrangement (MLLr) comprises a cellular hierarchy in which a subpopulation of cells serves as functional leukemia stem cells (LSCs). They are maintained by a unique gene expression program and chromatin states, which are thought to reflect the actions of enhancers. Here, we delineate the active enhancer landscape and observe pervasive enhancer malfunction in LSCs. Reconstruction of regulatory networks revealed a master set of hematopoietic transcription factors. We show that EP300 is an essential transcriptional coregulator for maintaining LSC oncogenic potential, as it controls essential gene expression through modulation of H3K27 acetylation and assessments of transcription factor dependencies. Moreover, the EP300 inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008787
  2. Front Oncol. 2022 ;12 1054233
    When cancer drug resistance meets metabolomics (bulk, single-cell and/or spatial): Progress, potential, and perspective.
    Zhiqiang Zhang, Chaohui Bao, Lu Jiang, Shan Wang, Kankan Wang, Chang Lu, Hai Fang.
      Resistance to drug treatment is a critical barrier in cancer therapy. There is an unmet need to explore cancer hallmarks that can be targeted to overcome this resistance for therapeutic gain. Over time, metabolic reprogramming has been recognised as one hallmark that can be used to prevent therapeutic resistance. With the advent of metabolomics, targeting metabolic alterations in cancer cells and host patients represents an emerging therapeutic strategy for overcoming cancer drug resistance. Driven by technological and methodological advances in mass spectrometry imaging, spatial metabolomics involves the profiling of all the metabolites (metabolomics) so that the spatial information is captured bona fide within the sample. Spatial metabolomics offers an opportunity to demonstrate the drug-resistant tumor profile with metabolic heterogeneity, and also poses a data-mining challenge to reveal meaningful insights from high-dimensional spatial information. In this review, we discuss the latest progress, with the focus on currently available bulk, single-cell and spatial metabolomics technologies and their successful applications in pre-clinical and translational studies on cancer drug resistance. We provide a summary of metabolic mechanisms underlying cancer drug resistance from different aspects; these include the Warburg effect, altered amino acid/lipid/drug metabolism, generation of drug-resistant cancer stem cells, and immunosuppressive metabolism. Furthermore, we propose solutions describing how to overcome cancer drug resistance; these include early detection during cancer initiation, monitoring of clinical drug response, novel anticancer drug and target metabolism, immunotherapy, and the emergence of spatial metabolomics. We conclude by describing the perspectives on how spatial omics approaches (integrating spatial metabolomics) could be further developed to improve the management of drug resistance in cancer patients.
    Keywords:  cancer drug resistance; metabolic reprogramming; metabolomics; single-cell metabolomics; spatial metabolomics
    DOI:  https://doi.org/10.3389/fonc.2022.1054233
  3. Nature. 2023 Jan 25.
    A census of complexes formed by mitochondrial proteins.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-00095-0
  4. Front Oncol. 2022 ;12 1072739
    The promise of targeting heme and mitochondrial respiration in normalizing tumor microenvironment and potentiating immunotherapy.
    Zakia Akter, Narges Salamat, Md Yousuf Ali, Li Zhang.
      Cancer immunotherapy shows durable treatment responses and therapeutic benefits compared to other cancer treatment modalities, but many cancer patients display primary and acquired resistance to immunotherapeutics. Immunosuppressive tumor microenvironment (TME) is a major barrier to cancer immunotherapy. Notably, cancer cells depend on high mitochondrial bioenergetics accompanied with the supply of heme for their growth, proliferation, progression, and metastasis. This excessive mitochondrial respiration increases tumor cells oxygen consumption, which triggers hypoxia and irregular blood vessels formation in various regions of TME, resulting in an immunosuppressive TME, evasion of anti-tumor immunity, and resistance to immunotherapeutic agents. In this review, we discuss the role of heme, heme catabolism, and mitochondrial respiration on mediating immunosuppressive TME by promoting hypoxia, angiogenesis, and leaky tumor vasculature. Moreover, we discuss the therapeutic prospects of targeting heme and mitochondrial respiration in alleviating tumor hypoxia, normalizing tumor vasculature, and TME to restore anti-tumor immunity and resensitize cancer cells to immunotherapy.
    Keywords:  angiogenesis; cancer immunotherapy; heme; hypoxia; mitochondrial respiration; tumor micoenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1072739
  5. Adv Exp Med Biol. 2023 Jan 24.
    Cancer Stem Cells and Their Therapeutic Usage.
    Meryem Osum, Rasime Kalkan.
      Cancer stem cells (CSC) have unique characteristics which include self-renewal, multi-directional differentiation capacity, quiescence/dormancy, and tumor-forming capability. These characteristics are referred to as the "stemness" properties. Tumor microenvironment contributes to CSC survival, function, and remaining them in an undifferentiated state. CSCs can form malignant tumors with heterogeneous phenotypes mediated by the tumor microenvironment. Therefore, the crosstalk between CSCs and tumor microenvironment can modulate tumor heterogeneity. CSCs play a crucial role in several biological processes, epithelial-mesenchymal transition (EMT), autophagy, and cellular stress response. In this chapter, we focused characteristics of cancer stem cells, reprogramming strategies cells into CSCs, and then we highlighted the contribution of CSCs to therapy resistance and cancer relapse and their potential of therapeutic targeting of CSCs.
    Keywords:  Cancer stem cells; Therapeutic targeting; Treatment
    DOI:  https://doi.org/10.1007/5584_2022_758
  6. Front Oncol. 2022 ;12 1111724
    Editorial: Developing combined modality therapy with mitochondria-targeting strategy.
    Yong Teng.
      
    Keywords:  cancer; combined therapy; mitochondria and disease; targeting strategy; translational sciences
    DOI:  https://doi.org/10.3389/fonc.2022.1111724
  7. Cancer Metastasis Rev. 2023 Jan 25.
    The role of cancer cell bioenergetics in dormancy and drug resistance.
    Steven Tau, Todd W Miller.
      While anti-cancer drug treatments are often effective for the clinical management of cancer, these treatments frequently leave behind drug-tolerant persister cancer cells that can ultimately give rise to recurrent disease. Such persistent cancer cells can lie dormant for extended periods of time, going undetected by conventional clinical means. Understanding the mechanisms that such dormant cancer cells use to survive, and the mechanisms that drive emergence from dormancy, is critical to the development of improved therapeutic strategies to prevent and manage disease recurrence. Cancer cells often exhibit metabolic alterations compared to their non-transformed counterparts. An emerging body of evidence supports the notion that dormant cancer cells also have unique metabolic adaptations that may offer therapeutically targetable vulnerabilities. Herein, we review mechanisms through which cancer cells metabolically adapt to persist during drug treatments and develop drug resistance. We also highlight emerging therapeutic strategies to target dormant cancer cells via their metabolic features.
    Keywords:  Cancer; Energy; Fatty acid; Glucose; Metabolism; Tumor
    DOI:  https://doi.org/10.1007/s10555-023-10081-7
  8. Cell Rep. 2023 Jan 27. pii: S2211-1247(23)00052-9. [Epub ahead of print]42(2): 112041
    Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress.
    Ying Liu, Kejia Liu, Rick F Thorne, Ronghua Shi, Qingyuan Zhang, Mian Wu, Lianxin Liu.
      Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.
    Keywords:  CP: Cancer; CP: Metabolism; PTMs; SENP2; SUMOylation; TCA cycle; acetylation; metabolic stress; mitochondria; oxidative phosphorylation; succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112041
  9. Cell Res. 2023 Jan 24.
    Mitochondrial PD-L1 modulates cancer immunotherapy.
    Xiaoming Dai, Jing Liu, Wenyi Wei.
      
    DOI:  https://doi.org/10.1038/s41422-023-00777-4
  10. Cancer. 2023 Jan 24.
    AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.
    AVALON Cooperative Group
       BACKGROUND: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia.
    METHODS: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here.
    RESULTS: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event.
    CONCLUSIONS: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.
    Keywords:  acute myeloid leukemia; hypomethylating agents; real-life data; relapsed and refractory AML; venetoclax
    DOI:  https://doi.org/10.1002/cncr.34608
  11. Cell Death Dis. 2023 Jan 24. 14(1): 57
    To be or not to be a fat burner, that is the question for cpt1c in cancer cells.
    Rut Fadó, Sebastian Zagmutt, Laura Herrero, Helena Muley, Rosalía Rodríguez-Rodríguez, Huichang Bi, Dolors Serra, Núria Casals.
      There is an urgent need to identify reliable genetic biomarkers for accurate diagnosis, prognosis, and treatment of different tumor types. Described as a prognostic marker for many tumors is the neuronal protein carnitine palmitoyltransferase 1 C (CPT1C). Several studies report that CPT1C is involved in cancer cell adaptation to nutrient depletion and hypoxia. However, the molecular role played by CPT1C in cancer cells is controversial. Most published studies assume that, like canonical CPT1 isoforms, CPT1C is a mediator of fatty acid transport to mitochondria for beta-oxidation, despite the fact that CPT1C has inefficient catalytic activity and is located in the endoplasmic reticulum. In this review, we collate existing evidence on CPT1C in neurons, showing that CPT1C is a sensor of nutrients that interacts with and regulates other proteins involved in lipid metabolism and transport, lysosome motility, and the secretory pathway. We argue, therefore, that CPT1C expression in cancer cells is not a direct regulator of fat burn, but rather is a regulator of lipid metabolic reprograming and cell adaptation to environmental stressors. We also review the clinical relevance of CPT1C as a prognostic indicator and its contribution to tumor growth, cancer invasiveness, and cell senescence. This new and integrated vision of CPT1C function can help better understand the metabolic plasticity of cancer cells and improve the design of therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-023-05599-1
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