bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–01–17
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML.
  2. Enriching for human acute myeloid leukemia stem cells using reactive oxygen species-based cell sorting.
  3. Trends in survival of leukemia among children, adolescents and young adults: a population-based study in osaka, japan.
  4. Synthetic cyclopenta[b]indoles exhibit antineoplastic activity by targeting microtubule dynamics in acute myeloid leukemia cells.
  5. BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca2+-dependent mPTP opening.
  6. B7-H4 induces epithelial-mesenchymal transition and promotes colorectal cancer stemness.
  7. CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells.
  8. Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer.
  9. Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites.
  10. Concerted roles of PTEN and ATM in controlling hematopoietic stem cell fitness and dormancy.
  1. Nat Commun. 2021 01 11. 12(1): 245
    Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML.
    Toshihiko Oki, Francois Mercier, Hiroki Kato, Yookyung Jung, Thomas O McDonald, Joel A Spencer, Michael C Mazzola, Nick van Gastel, Charles P Lin, Franziska Michor, Toshio Kitamura, David T Scadden.
      Acute myeloid leukemia (AML) is a high remission, high relapse fatal blood cancer. Although mTORC1 is a master regulator of cell proliferation and survival, its inhibitors have not performed well as AML treatments. To uncover the dynamics of mTORC1 activity in vivo, fluorescent probes are developed to track single cell proliferation, apoptosis and mTORC1 activity of AML cells in the bone marrow of live animals and to quantify these activities in the context of microanatomical localization and intra-tumoral heterogeneity. When chemotherapy drugs commonly used clinically are given to mice with AML, apoptosis is rapid, diffuse and not preferentially restricted to anatomic sites. Dynamic measurement of mTORC1 activity indicated a decline in mTORC1 activity with AML progression. However, at the time of maximal chemotherapy response, mTORC1 signaling is high and positively correlated with a leukemia stemness transcriptional profile. Cell barcoding reveals the induction of mTORC1 activity rather than selection of mTORC1 high cells and timed inhibition of mTORC1 improved the killing of AML cells. These data define the real-time dynamics of AML and the mTORC1 pathway in association with AML growth, response to and relapse after chemotherapy. They provide guidance for timed intervention with pathway-specific inhibitors.
    DOI:  https://doi.org/10.1038/s41467-020-20491-8
  2. STAR Protoc. 2021 Mar 19. 2(1): 100248
    Enriching for human acute myeloid leukemia stem cells using reactive oxygen species-based cell sorting.
    Brett M Stevens, Cristiana O'Brien, Craig T Jordan, Courtney L Jones.
      Isolation of leukemia stem cells presents a challenge due to the heterogeneity of the immunophenotypic markers commonly used to identify blood stem cells. Several studies have reported that relative levels of reactive oxygen species (ROS) can be used to enrich for stem cell populations, suggesting a potential alternative to surface antigen-based methods. Here, we describe a protocol to enrich for stem cells from human acute myeloid leukemia specimens using relative levels of ROS. This protocol provides consistent enrichment of leukemia stem cells. For complete details on the use and execution of this protocol, please refer to Lagadinou et al. (2013) and Pei et al. (2018).
    Keywords:  Cancer; Flow cytometry/mass cytometry; Metabolism; Stem cells
    DOI:  https://doi.org/10.1016/j.xpro.2020.100248
  3. Cancer Sci. 2021 Jan 11.
    Trends in survival of leukemia among children, adolescents and young adults: a population-based study in osaka, japan.
    Osaka Cancer Association for Children Adolescents Young Adults
      This study focused on children, adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population-based cancer registry data from Osaka, Japan. The study subjects comprised 2,254 children (0-14 years) and 2,905 AYAs (15-39 years) who were diagnosed with leukemia during 1975-2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed five-year overall survival probability (5y-OS), using the Kaplan-Meier method and expressed time trends using Joinpoint regression model. For recently-diagnosed (2006-2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y-OS, using age group, gender and treatment hospital as covariates. Over the 37 year-period, 5y-OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y-OS from ALL improved, especially after 2000 (65% in 2006-2011) when the pediatric regimen was introduced but was still lower than that among children (87% in 2006-2011, p<0.001). Survival improvement was most remarkable in CML and its 5y-OS was over 90% among both children and AYAs after the introduction of molecularly targeted therapy with tyrosine kinase inhibitors. Among patients with recently-diagnosed AML, the risk of death was significantly higher for patients treated at non-designated hospitals than those treated at designated cancer care hospitals. The changes in survival improvement coincided with the introduction of treatment regimens or molecularly targeted therapies. Patient centralization might be one option which would improve survival.
    Keywords:  adolescents and young adults; children; epidemiology; leukemia; survival
    DOI:  https://doi.org/10.1111/cas.14808
  4. Eur J Pharmacol. 2021 Jan 08. pii: S0014-2999(21)00006-6. [Epub ahead of print]894 173853
    Synthetic cyclopenta[b]indoles exhibit antineoplastic activity by targeting microtubule dynamics in acute myeloid leukemia cells.
    Hugo Passos Vicari, Keli Lima, Ralph da Costa Gomes, Daniara Cristina Fernandes, Jean Carlos Lipreri da Silva, Manoel Trindade Rodrigues Junior, Aline Silva Barroso de Oliveira, Ricardo Nascimento Dos Santos, Adriano Defini Andricopulo, Fernando Coelho, Leticia Veras Costa-Lotufo, João Agostinho Machado-Neto.
      Acute promyelocytic leukemia (APL) is associated with PML-RARα oncogene, which is treated using all-trans retinoic acid (ATRA)-based chemotherapy. However, chemoresistance is observed in 20-30% of treated patients and represents a clinical challenge, raising the importance of the development of new therapeutic options. In the present study, the effects of three synthetic cyclopenta[b]indoles on the leukemia phenotype were investigated using NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Among the tested synthetic cyclopenta[b]indoles, compound 2, which contains a heterocyclic nucleus, was the most active, presenting time-dependent cytotoxic activity in the μM range in APL cells, without cytotoxicity for normal leukocytes, and was selected for further characterization. Compound 2 significantly decreased clonogenicity, increased apoptosis, and caused cell cycle arrest at S and G2/M phases in a drug concentration-dependent manner. Morphological analyses indicated aberrant mitosis and diffuse tubulin staining upon compound 2 exposure, which corroborates cell cycle findings. In the molecular scenario, compound 2 reduced STMN1 expression and activity, and induced PARP1 cleavage and H2AX and CHK2 phosphorylation, and modulated CDKN1A, PMAIP1, GADD45A, and XRCC3 expressions, indicating reduction of cell proliferation, apoptosis, and DNA damage. Moreover, in the in vivo tubulin polymerization assay, NB4 and NB4-R2 cells showed a reduction in the levels of polymerized tubulin upon compound 2 exposure, which indicates tubulin as a target of the drug. Molecular docking supports this hypothesis. Taken together, these data indicated that compound 2 exhibits antileukemic effects through disrupting the microtubule dynamics, identifying a possible novel potential antineoplastic agent for the treatment of ATRA-resistant APL.
    Keywords:  Acute promyelocytic leukemia; Chemotherapy resistance; Microtubule dynamics; cyclopenta[b]indoles
    DOI:  https://doi.org/10.1016/j.ejphar.2021.173853
  5. Cell Calcium. 2021 Jan 12. pii: S0143-4160(20)30175-5. [Epub ahead of print]94 102333
    BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca2+-dependent mPTP opening.
    Martijn Kerkhofs, Rita La Rovere, Kirsten Welkenhuysen, Ann Janssens, Peter Vandenberghe, Muniswamy Madesh, Jan B Parys, Geert Bultynck.
      Anti-apoptotic Bcl-2 critically controls cell death by neutralizing pro-apoptotic Bcl-2-family members at the mitochondria. Bcl-2 proteins also act at the endoplasmic reticulum, the main intracellular Ca2+-storage organelle, where they inhibit IP3 receptors (IP3R) and prevent pro-apoptotic Ca2+-signaling events. IP3R channels are targeted by the BH4 domain of Bcl-2. Some cancer types rely on the IP3R-Bcl-2 interaction for survival. We previously developed a cell-permeable, BH4-domain-targeting peptide that can abrogate Bcl-2's inhibitory action on IP3Rs, named Bcl-2 IP3 receptor disrupter-2 (BIRD-2). This peptide kills several Bcl-2-dependent cancer cell types, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukaemia (CLL) cells, by eliciting intracellular Ca2+ signalling. However, the exact mechanisms by which these excessive Ca2+ signals triggered by BIRD-2 provoke cancer cell death remain elusive. Here, we demonstrate in DLBCL that although BIRD-2 activates caspase 3/7 and provokes cell death in a caspase-dependent manner, the cell death is independent of pro-apoptotic Bcl-2-family members, Bim, Bax and Bak. Instead, BIRD-2 provokes mitochondrial Ca2+ overload that is rapidly followed by opening of the mitochondrial permeability transition pore (mPTP). Inhibiting mitochondrial Ca2+ overload using Ru265, an inhibitor of the mitochondrial Ca2+ uniporter complex counteracts BIRD-2-induced cancer cell death. Finally, we validated our findings in primary CLL patient samples where BIRD-2 provoked mitochondrial Ca2+ overload and Ru265 counteracted BIRD-2-induced cell death. Overall, this work reveals the mechanisms by which BIRD-2 provokes cell death, which occurs via mitochondrial Ca2+ overload but acts independently of pro-apoptotic Bcl-2-family members.
    Keywords:  Apoptosis; B-cell lymphoma 2; Calcium signaling; Mitochondrial permeability transition pore; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ceca.2020.102333
  6. Pathol Res Pract. 2021 Jan 02. pii: S0344-0338(20)32178-6. [Epub ahead of print]218 153323
    B7-H4 induces epithelial-mesenchymal transition and promotes colorectal cancer stemness.
    Ying Feng, Zhaoting Yang, Chengye Zhang, Nan Che, Xingzhe Liu, Yanhua Xuan.
      B7-H4 is a unique negative regulator of T cells that is typically significantly overexpressed in various carcinomas and is associated with poor prognosis. However, the effects of B7-H4 expression on epithelial-mesenchymal transition (EMT) and cancer stemness of colorectal cancer (CRC) are not entirely clear. In the present study, we used tissue samples from 98 patients with CRC and CRC cell lines to determine the clinicopathological significance of B7-H4 in CRC and its effects on CRC stemness. We performed immunohistochemical staining; immunofluorescence imaging; western blotting; and tumor sphere formation, wound healing, transwell migration, and in vivo tumorigenesis assays. B7-H4 expression was upregulated in CRC tissues and was associated with lymph node metastasis, distant metastasis, clinical stage, a shorter overall survival rate, and disease-free survival rate. Cox regression analyses indicated that B7-H4 is an independent poor prognostic factor for CRC. In addition, B7-H4 expression was correlated with the expression of EMT-related proteins and cancer stemness-related proteins. Moreover, immunohistochemical and immunofluorescence analyses revealed that B7-H4 was correlated with CD133 and CD44 expression levels in both CRC tissues and HT29 and HCT116 cell lines. Conversely, B7-H4 knockdown downregulated the expression of EMT- and cancer stemness-related proteins, while inhibiting tumor spheroid formation, cell migration, and invasion of CRC cell lines. These results indicate that B7-H4 can promote EMT and may be a novel stem cell marker, suggesting its potential as a prognostic biomarker for CRC.
    Keywords:  B7-H4; Cancer stemness; Colorectal cancer; Epithelial-mesenchymal transition; Prognostic
    DOI:  https://doi.org/10.1016/j.prp.2020.153323
  7. Nat Commun. 2021 01 11. 12(1): 240
    CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells.
    Mario Bunse, Janina Pfeilschifter, Julia Bluhm, Maria Zschummel, Jara J Joedicke, Anthea Wirges, Helen Stark, Vivien Kretschmer, Markus Chmielewski, Wolfgang Uckert, Hinrich Abken, Jörg Westermann, Armin Rehm, Uta E Höpken.
      CAR-T cell therapy targeting CD19 demonstrated strong activity against advanced B cell leukemia, however shows less efficacy against lymphoma with nodal dissemination. To target both B cell Non-Hodgkin's lymphoma (B-NHLs) and follicular T helper (Tfh) cells in the tumor microenvironment (TME), we apply here a chimeric antigen receptor (CAR) that recognizes human CXCR5 with high avidity. CXCR5, physiologically expressed on mature B and Tfh cells, is also highly expressed on nodal B-NHLs. Anti-CXCR5 CAR-T cells eradicate B-NHL cells and lymphoma-supportive Tfh cells more potently than CD19 CAR-T cells in vitro, and they efficiently inhibit lymphoma growth in a murine xenograft model. Administration of anti-murine CXCR5 CAR-T cells in syngeneic mice specifically depletes endogenous and malignant B and Tfh cells without unexpected on-target/off-tumor effects. Collectively, anti-CXCR5 CAR-T cells provide a promising treatment strategy for nodal B-NHLs through the simultaneous elimination of lymphoma B cells and Tfh cells of the tumor-supporting TME.
    DOI:  https://doi.org/10.1038/s41467-020-20488-3
  8. Mol Cell Proteomics. 2019 Feb;pii: S1535-9476(20)31868-5. [Epub ahead of print]18(2): 231-244
    Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer.
    Etna Abad, Yoelsis García-Mayea, Cristina Mir, David Sebastian, Antonio Zorzano, David Potesil, Zbynek Zdrahal, Alex Lyakhovich, Matilde E Lleonart.
      Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumor growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumor growth. This study puts mitochondria in a spotlight for cancer therapy and places antibiotics as effective agents for eliminating CSC and resistant cells.
    Keywords:  Antibiotics; Autophagy; Breast Cancer; Cancer Biology; Cancer Stem Cells; Chemoresistance; Clinical Proteomics; Mitochondria; Mitochondria Function or Biology; NMR; NMR-metabolomic; Stem Cells
    DOI:  https://doi.org/10.1074/mcp.RA118.001102
  9. Int J Mol Sci. 2021 Jan 12. pii: E697. [Epub ahead of print]22(2):
    Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites.
    Kenneth K Wu.
      Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases.
    Keywords:  5-methoxytryptophan; antioxidant enzymes; cellular senescence mitochondrial dysfunction; hyperglycemia; melatonin; mesenchymal stromal/stem cells; reactive oxygen species; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms22020697
  10. J Clin Invest. 2021 Jan 14. pii: 131698. [Epub ahead of print]
    Concerted roles of PTEN and ATM in controlling hematopoietic stem cell fitness and dormancy.
    Jerome Fortin, Christian Bassi, Parameswaran Ramachandran, Wanda Y Li, Ruxiao Tian, Ida Zarrabi, Graham Hill, Bryan E Snow, Jillian Haight, Chantal Tobin, Kelsey Hodgson, Andrew Wakeham, Vuk Stambolic, Tak W Mak.
      In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms to preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting their survival, self-renewal and differentiation. Ablation of the kinase ATM, a master regulator of the DNA damage response, impairs HSC fitness. Paradoxically, we show here that loss of a single allele of Atm enhances HSC functionality in mice. To explain this observation, we explored a possible link between ATM and the tumor suppressor PTEN, which also regulates HSC function. We generated and analyzed a knock-in mouse line (PtenS398A/S398A), in which PTEN cannot be phosphorylated by ATM. Similar to Atm+/-, PtenS398A/S398A HSCs have enhanced hematopoietic reconstitution ability, accompanied by resistance to apoptosis induced by genotoxic stress. Single-cell transcriptomic analyses and functional assays revealed that dormant PtenS398A/S398A HSCs aberrantly tolerate elevated mitochondrial activity and the accumulation of reactive oxygen species, which are normally associated with HSC priming for self-renewal or differentiation. Our results unveil a molecular connection between ATM and PTEN, which couples the response to genotoxic stress and dormancy in HSC.
    Keywords:  DNA repair; Hematology; Hematopoietic stem cells; Stem cells
    DOI:  https://doi.org/10.1172/JCI131698
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