bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022‒02‒06
ten papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.
  2. Dysregulated lipid metabolism in colorectal cancer.
  3. Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response.
  4. Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy.
  5. Dangerous dynamic duo: Lactic acid and PD-1 blockade.
  6. Advancing Cancer Therapy.
  7. CORRIGENDUM to "A 15-color panel for immunophenotypic identification, quantification and characterization of leukemic stem cells in children with acute myeloid leukemia" published in Cytometry Part A, 26 December 2020, https://doi.org/10.1002/cyto.a.24284.
  8. The role of SOX family in cancer stem cell maintenance: With a focus on SOX2.
  9. Lighting up the tumor fire with low-dose irradiation.
  10. Identification of six hub genes and analysis of their correlation with drug sensitivity in acute myeloid leukemia through bioinformatics.
  1. Nat Cancer. 2021 Nov;2(11): 1204-1223
    Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.
    Claudie Bosc, Estelle Saland, Aurélie Bousard, Noémie Gadaud, Marie Sabatier, Guillaume Cognet, Thomas Farge, Emeline Boet, Mathilde Gotanègre, Nesrine Aroua, Pierre-Luc Mouchel, Nathaniel Polley, Clément Larrue, Eléonore Kaphan, Muriel Picard, Ambrine Sahal, Latifa Jarrou, Marie Tosolini, Florian Rambow, Florence Cabon, Nathalie Nicot, Laura Poillet-Perez, Yujue Wang, Xiaoyang Su, Quentin Fovez, Jérôme Kluza, Rafael José Argüello, Céline Mazzotti, Hervé Avet-Loiseau, François Vergez, Jérôme Tamburini, Jean-Jacques Fournié, Ing S Tiong, Andrew H Wei, Tony Kaoma, Jean-Christophe Marine, Christian Récher, Lucille Stuani, Carine Joffre, Jean-Emmanuel Sarry.
      Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.
    DOI:  https://doi.org/10.1038/s43018-021-00264-y
  2. Curr Opin Gastroenterol. 2022 Mar 01. 38(2): 162-167
    Dysregulated lipid metabolism in colorectal cancer.
    Olivia Coleman, Miriam Ecker, Dirk Haller.
      PURPOSE OF REVIEW: Lipid metabolism presents a targetable metabolic vulnerability in colorectal cancer (CRC). Lipid signatures and cancer-cell lipid requirements may serve as noninvasive diagnostic and prognostic biomarkers and as a therapeutic target, respectively.RECENT FINDINGS: A growing body of new studies highlight the complexity of lipid metabolism in CRC. Cancer cells are able to utilize an alternative fatty acid desaturation pathway, underlining the metabolic plasticity of tumors. CRC tissue shows a robust triglyceride-species signature with prognostic value in CRC patients. Lipidomic analyses in germfree and colonized mice identify a unique lipid signature and suggest that bacteria inhibit metabolism of polyunsaturated fatty acids by blocking desaturase and elongase activities. Cellular stress responses, particularly the well characterized unfolded protein response, are involved in regulating lipid synthesis and homeostasis, and contribute to adaptation of the lipid environment. Together, lipid metabolism, the intestinal microbiota and cellular stress responses unarguably play crucial roles in CRC.
    SUMMARY: A number of recent advances in our understanding of dysregulated lipid metabolism in CRC underline the importance of this research field. An improved knowledge of the complex interplay between lipid metabolism, cellular stress and the intestinal microbiota in the context of CRC may lead to novel therapeutic strategies.
    DOI:  https://doi.org/10.1097/MOG.0000000000000811
  3. Nat Cancer. 2021 May;2(5): 527-544
    Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response.
    Marina Scheller, Anne Kathrin Ludwig, Stefanie Göllner, Christian Rohde, Stephen Krämer, Sina Stäble, Maike Janssen, James-Arne Müller, Lixiazi He, Nicole Bäumer, Christian Arnold, Joachim Gerß, Maximilian Schönung, Christian Thiede, Christian Niederwieser, Dietger Niederwieser, Hubert Serve, Wolfgang E Berdel, Ulrich Thiem, Inga Hemmerling, Florian Leuschner, Christoph Plass, Matthias Schlesner, Judith Zaugg, Michael D Milsom, Andreas Trumpp, Caroline Pabst, Daniel B Lipka, Carsten Müller-Tidow.
      Somatic mutations in DNA methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and acute myeloid leukemia (AML), with a hotspot in exon 23 at arginine 882 (DNMT3AR882). Here, we demonstrate that DNMT3AR882H-dependent CH and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in individuals with DNMT3AR882 mutations, suggesting its potential as a predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3AR882H-expressing cells. Hematopoietic stem cells (HSCs) and progenitor cells expressing DNMT3AR882H exhibited cell autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically in DNMT3AR882H-expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.
    DOI:  https://doi.org/10.1038/s43018-021-00213-9
  4. SAGE Open Med. 2022 ;10 20503121211069012
    Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy.
    Bhalchandra Mirlekar.
      Cytokines play a critical role in regulating host immune response toward cancer and determining the overall fate of tumorigenesis. The tumor microenvironment is dominated mainly by immune-suppressive cytokines that control effector antitumor immunity and promote survival and the proliferation of cancer cells, which ultimately leads to enhanced tumor growth. In addition to tumor cells, the heterogeneous immune cells present within the tumor milieu are the significant source of immune-suppressive cytokines. These cytokines are classified into a broad range; however, in most tumor types, the interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 are consistently reported as immune-suppressive cytokines that help tumor growth and metastasis. The most emerging concern in cancer treatment is hijacking and restraining the activity of antitumor immune cells in the tumor niche due to a highly immune-suppressive environment. This review summarizes the role and precise functions of interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 in modulating tumor immune contexture and its implication in developing effective immune-therapeutic approaches.Concise conclusion: Recent effort geared toward developing novel immune-therapeutic approaches faces significant challenges due to sustained mutations in tumor cells and a highly immune-suppressive microenvironment present within the tumor milieu. The cytokines play a crucial role in developing an immune-suppressive environment that ultimately dictates the fate of tumorigenesis. This review critically covers the novel aspects of predominant immune-suppressive cytokines such as interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 in dictating the fate of tumorigenesis and how targeting these cytokines can help the development of better immune-therapeutic drug regimens for the treatment of cancer.
    Keywords:  Immune-suppressive cytokines; antitumor immunity; cancer immunotherapy; tumor growth; tumor microenvironment
    DOI:  https://doi.org/10.1177/20503121211069012
  5. Cancer Cell. 2022 Jan 28. pii: S1535-6108(22)00010-1. [Epub ahead of print]
    Dangerous dynamic duo: Lactic acid and PD-1 blockade.
    Sheila Johnson, Marcia C Haigis, Stephanie K Dougan.
      In this issue of Cancer Cell, Kumagai et al. reveal lactic acid as a mediator of checkpoint blockade resistance. Tumor-derived lactic acid promotes T regulatory cell (Treg) activity and impairs CD8+ T cell function. PD-1 blockade synergizes with lactic acid to enhance Treg suppression and impede antitumor immunity.
    DOI:  https://doi.org/10.1016/j.ccell.2022.01.008
  6. Nat Cancer. 2021 Mar;2(3): 245-246
    Advancing Cancer Therapy.
      
    DOI:  https://doi.org/10.1038/s43018-021-00192-x
  7. Cytometry A. 2022 Feb 01.
    CORRIGENDUM to "A 15-color panel for immunophenotypic identification, quantification and characterization of leukemic stem cells in children with acute myeloid leukemia" published in Cytometry Part A, 26 December 2020, https://doi.org/10.1002/cyto.a.24284.
      
    DOI:  https://doi.org/10.1002/cyto.a.24538
  8. Pathol Res Pract. 2022 Jan 29. pii: S0344-0338(22)00026-7. [Epub ahead of print]231 153783
    The role of SOX family in cancer stem cell maintenance: With a focus on SOX2.
    Farhad Pouremamali, Vahid Vahedian, Nasrin Hassani, Sepideh Mirzaei, Amir Pouremamali, Hamid Kazemzadeh, Yousef Faridvand, Davoud Jafari-Gharabaghlou, Mohammad Nouri, Nazila Fathi Maroufi.
      The role of cancer stem cells (CSCs) in cancer incidence, drug resistance, and relapse after chemotherapy has been discussed and it has been confirmed that CSCs are extremely important and so, are suitable for therapeutic targeting. Sox families play an important role in carcinogenesis and dis-regulation of SOXs molecules has been observed in different types of cancers. The members of this family have been shown to play an important role in the maintenance of CSCs. In this article, we have tried to evaluate the role of different family members in CSCs maintenance, review various studies in this field and provide a perspective view on this issue. Also, due to the important role and many studies in the field of SOX2 molecule in CSCs, we try to have more focus on this molecule and examine the potential of these molecules for therapeutic targeting.
    Keywords:  Cancer Stem Cells; Drug resistance; Maintenance; SOX family; SOX2
    DOI:  https://doi.org/10.1016/j.prp.2022.153783
  9. Trends Immunol. 2022 Jan 29. pii: S1471-4906(22)00006-0. [Epub ahead of print]
    Lighting up the tumor fire with low-dose irradiation.
    Fernanda G Herrera, Pedro Romero, George Coukos.
      Current efforts combining immunotherapy and radiation have focused on high-dose radiation delivered to few tumor lesions, aiming to generate diffuse abscopal effects; however, these effects are uncommon in patients. Three recent studies in mouse tumor models and human cancer patients show that low-dose radiation (LDRT) delivered to all tumor lesions effectively mobilizes innate and adaptive immunity and synergizes with immunotherapy. These new findings suggest LDRT's potential as an immune amplifier capable of reprogramming the tumor microenvironment, instigating inflammation, and sensitizing 'cold' tumors to immune checkpoint blockade responsiveness.
    Keywords:  CD40L; CTLA-4; PD-1; immune checkpoint inhibitors; immunotherapy; low-dose radiation
    DOI:  https://doi.org/10.1016/j.it.2022.01.006
  10. Transl Cancer Res. 2021 Jan;10(1): 126-140
    Identification of six hub genes and analysis of their correlation with drug sensitivity in acute myeloid leukemia through bioinformatics.
    Daxia Cai, Jiajian Liang, Xing-Dong Cai, Ying Yang, Gexiu Liu, Fenling Zhou, Dongmei He.
      Background: Acute myeloid leukemia (AML) is a common hematopoietic malignancy and have unsatisfactory prognosis. Our study aimed to identify hub genes in AML and explore potential biomarkers through integrated bioinformatics.Methods: Microarray datasets were analyzed to screen the differentially expressed genes (DEGs). Functional enrichment analysis was performed, and protein-protein interaction (PPI) network was generated by the STRING (11.0) database and Cytoscape (3.7.2) software. Hub genes were screened and verified through GEPIA2 and GEO microarray database. Sensitivity of AML cell lines with high expression of hub genes to the small-molecule drugs were identified using GSCA Lite.
    Results: A total of 456 DEGs were identified and top 100 genes were screened out, of which six genes (FLT3, PF4, CD163, MRC1, CSF2RB, PPBP) were upregulated in AML and individually had a worse prognosis by the overall survival (OS) analysis. AML cell lines with FLT3-overexpression and CSF2RB-overexpression were sensitive to most small-molecule drugs, while, AML cells with CD163-overexpression were only sensitive to a few drugs. However, sensitivity to Erlotinib was correlated with high expression of PF4 and PPBP.
    Conclusions: In summary, FLT3, PF4, CD163, MRC1, CSF2RB, PPBP may be potential biomarkers and potential sensitive small-molecule drugs were correlated with overexpression of the biomarkers in AML.
    Keywords:  Acute myeloid leukemia (AML); differentially expressed genes (DEGs); drug sensitivity; survival
    DOI:  https://doi.org/10.21037/tcr-20-2712
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