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  1. Article: Protein Kinase C Epsilon Overexpression Is Associated With Poor Patient Outcomes in AML and Promotes Daunorubicin Resistance Through p-Glycoprotein-Mediated Drug Efflux.

    Nicholson, Rachael / Menezes, Ana Catarina / Azevedo, Aleksandra / Leckenby, Adam / Davies, Sara / Seedhouse, Claire / Gilkes, Amanda / Knapper, Steve / Tonks, Alex / Darley, Richard L

    Frontiers in oncology

    2022  Volume 12, Page(s) 840046

    Abstract: The protein kinase C (PKC) family of serine/threonine kinases are pleiotropic signaling regulators and are implicated in hematopoietic signaling and development. Only one isoform however, PKCϵ, has oncogenic properties in solid cancers where it is ... ...

    Abstract The protein kinase C (PKC) family of serine/threonine kinases are pleiotropic signaling regulators and are implicated in hematopoietic signaling and development. Only one isoform however, PKCϵ, has oncogenic properties in solid cancers where it is associated with poor outcomes. Here we show that PKCϵ protein is significantly overexpressed in acute myeloid leukemia (AML; 37% of patients). In addition, PKCϵ expression in AML was associated with a significant reduction in complete remission induction and disease-free survival. Examination of the functional consequences of PKCϵ overexpression in normal human hematopoiesis, showed that PKCϵ promotes myeloid differentiation, particularly of the monocytic lineage, and decreased colony formation, suggesting that PKCϵ does not act as an oncogene in hematopoietic cells. Rather, in AML cell lines, PKCϵ overexpression selectively conferred resistance to the chemotherapeutic agent, daunorubicin, by reducing intracellular concentrations of this agent. Mechanistic analysis showed that PKCϵ promoted the expression of the efflux pump, P-GP (ABCB1), and that drug efflux mediated by this transporter fully accounted for the daunorubicin resistance associated with PKCϵ overexpression. Analysis of AML patient samples also showed a link between PKCϵ and P-GP protein expression suggesting that PKCϵ expression drives treatment resistance in AML by upregulating P-GP expression.
    Language English
    Publishing date 2022-05-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2022.840046
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Increased expression of RUNX3 inhibits normal human myeloid development.

    Menezes, Ana Catarina / Jones, Rachel / Shrestha, Alina / Nicholson, Rachael / Leckenby, Adam / Azevedo, Aleksandra / Davies, Sara / Baker, Sarah / Gilkes, Amanda F / Darley, Richard L / Tonks, Alex

    Leukemia

    2022  Volume 36, Issue 7, Page(s) 1769–1780

    Abstract: RUNX3 is a transcription factor dysregulated in acute myeloid leukemia (AML). However, its role in normal myeloid development and leukemia is poorly understood. Here we investigate RUNX3 expression in both settings and the impact of its dysregulation on ... ...

    Abstract RUNX3 is a transcription factor dysregulated in acute myeloid leukemia (AML). However, its role in normal myeloid development and leukemia is poorly understood. Here we investigate RUNX3 expression in both settings and the impact of its dysregulation on myelopoiesis. We found that RUNX3 mRNA expression was stable during hematopoiesis but decreased with granulocytic differentiation. In AML, RUNX3 mRNA was overexpressed in many disease subtypes, but downregulated in AML with core binding factor abnormalities, such as RUNX1::ETO. Overexpression of RUNX3 in human hematopoietic stem and progenitor cells (HSPC) inhibited myeloid differentiation, particularly of the granulocytic lineage. Proliferation and myeloid colony formation were also inhibited. Conversely, RUNX3 knockdown did not impact the myeloid growth and development of human HSPC. Overexpression of RUNX3 in the context of RUNX1::ETO did not rescue the RUNX1::ETO-mediated block in differentiation. RNA-sequencing showed that RUNX3 overexpression downregulates key developmental genes, such as KIT and RUNX1, while upregulating lymphoid genes, such as KLRB1 and TBX21. Overall, these data show that increased RUNX3 expression observed in AML could contribute to the developmental arrest characteristic of this disease, possibly by driving a competing transcriptional program favoring a lymphoid fate.
    MeSH term(s) Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor Alpha 2 Subunit/metabolism ; Core Binding Factor Alpha 3 Subunit/genetics ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Oncogene Proteins, Fusion/genetics ; RNA, Messenger ; RUNX1 Translocation Partner 1 Protein/genetics ; Translocation, Genetic
    Chemical Substances Core Binding Factor Alpha 2 Subunit ; Core Binding Factor Alpha 3 Subunit ; Oncogene Proteins, Fusion ; RNA, Messenger ; RUNX1 Translocation Partner 1 Protein ; Runx3 protein, human
    Language English
    Publishing date 2022-04-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-022-01577-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2295: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: RUNX3 overexpression inhibits normal human erythroid development.

    Menezes, Ana Catarina / Dixon, Christabel / Scholz, Anna / Nicholson, Rachael / Leckenby, Adam / Azevedo, Aleksandra / Baker, Sarah / Gilkes, Amanda F / Davies, Sara / Darley, Richard L / Tonks, Alex

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 1243

    Abstract: RUNX proteins belong to a family of transcription factors essential for cellular proliferation, differentiation, and apoptosis with emerging data implicating RUNX3 in haematopoiesis and haematological malignancies. Here we show that RUNX3 plays an ... ...

    Abstract RUNX proteins belong to a family of transcription factors essential for cellular proliferation, differentiation, and apoptosis with emerging data implicating RUNX3 in haematopoiesis and haematological malignancies. Here we show that RUNX3 plays an important regulatory role in normal human erythropoiesis. The impact of altering RUNX3 expression on erythropoiesis was determined by transducing human CD34
    MeSH term(s) Cells, Cultured ; Core Binding Factor Alpha 3 Subunit/metabolism ; Erythroid Cells ; Erythropoiesis ; Humans ; Stem Cells
    Chemical Substances Core Binding Factor Alpha 3 Subunit ; Runx3 protein, human
    Language English
    Publishing date 2022-01-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-05371-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity.

    Guirguis, Andrew A / Ofir-Rosenfeld, Yaara / Knezevic, Kathy / Blackaby, Wesley / Hardick, David / Chan, Yih-Chih / Motazedian, Ali / Gillespie, Andrea / Vassiliadis, Dane / Lam, Enid Y N / Tran, Kevin / Andrews, Byron / Harbour, Michael E / Vasiliauskaite, Lina / Saunders, Claire J / Tsagkogeorga, Georgia / Azevedo, Aleksandra / Obacz, Joanna / Pilka, Ewa S /
    Carkill, Marie / MacPherson, Laura / Wainwright, Elanor N / Liddicoat, Brian / Blyth, Benjamin J / Albertella, Mark R / Rausch, Oliver / Dawson, Mark A

    Cancer discovery

    2023  Volume 13, Issue 10, Page(s) 2228–2247

    Abstract: Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA ... ...

    Abstract Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl-transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti-PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the mole-cular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.
    Significance: This work demonstrates that METTL3 inhibition stimulates a cell-intrinsic interferon response through dsRNA formation. This immunomodulatory mechanism is distinct from current immunotherapeutic agents and provides the molecular rationale for combination with anti-PD-1 immune-checkpoint blockade to augment antitumor immunity. This article is featured in Selected Articles from This Issue, p. 2109.
    MeSH term(s) Animals ; Mice ; Interferons/genetics ; Methyltransferases/genetics ; Methyltransferases/metabolism ; RNA, Double-Stranded
    Chemical Substances Interferons (9008-11-1) ; Methyltransferases (EC 2.1.1.-) ; RNA, Double-Stranded
    Language English
    Publishing date 2023-08-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-23-0007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6916: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Gata2 as a Crucial Regulator of Stem Cells in Adult Hematopoiesis and Acute Myeloid Leukemia.

    Menendez-Gonzalez, Juan Bautista / Vukovic, Milica / Abdelfattah, Ali / Saleh, Lubaid / Almotiri, Alhomidi / Thomas, Leigh-Anne / Agirre-Lizaso, Aloña / Azevedo, Aleksandra / Menezes, Ana Catarina / Tornillo, Giusy / Edkins, Sarah / Kong, Kay / Giles, Peter / Anjos-Afonso, Fernando / Tonks, Alex / Boyd, Ashleigh S / Kranc, Kamil R / Rodrigues, Neil P

    Stem cell reports

    2019  Volume 13, Issue 2, Page(s) 291–306

    Abstract: Subversion of transcription factor (TF) activity in hematopoietic stem/progenitor cells (HSPCs) leads to the development of therapy-resistant leukemic stem cells (LSCs) that drive fulminant acute myeloid leukemia (AML). Using a conditional mouse model ... ...

    Abstract Subversion of transcription factor (TF) activity in hematopoietic stem/progenitor cells (HSPCs) leads to the development of therapy-resistant leukemic stem cells (LSCs) that drive fulminant acute myeloid leukemia (AML). Using a conditional mouse model where zinc-finger TF Gata2 was deleted specifically in hematopoietic cells, we show that knockout of Gata2 leads to rapid and complete cell-autonomous loss of adult hematopoietic stem cells. By using short hairpin RNAi to target GATA2, we also identify a requirement for GATA2 in human HSPCs. In Meis1a/Hoxa9-driven AML, deletion of Gata2 impedes maintenance and self-renewal of LSCs. Ablation of Gata2 enforces an LSC-specific program of enhanced apoptosis, exemplified by attenuation of anti-apoptotic factor BCL2, and re-instigation of myeloid differentiation--which is characteristically blocked in AML. Thus, GATA2 acts as a critical regulator of normal and leukemic stem cells and mediates transcriptional networks that may be exploited therapeutically to target key facets of LSC behavior in AML.
    MeSH term(s) Animals ; Apoptosis ; Cell Self Renewal ; Disease Models, Animal ; GATA2 Transcription Factor/antagonists & inhibitors ; GATA2 Transcription Factor/genetics ; GATA2 Transcription Factor/metabolism ; Hematopoiesis ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Kaplan-Meier Estimate ; Leukemia, Myeloid, Acute/mortality ; Leukemia, Myeloid, Acute/pathology ; Leukemia, Myeloid, Acute/therapy ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplastic Stem Cells/cytology ; Neoplastic Stem Cells/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism
    Chemical Substances GATA2 Transcription Factor ; Gata2 protein, mouse ; Proto-Oncogene Proteins c-bcl-2 ; RNA, Small Interfering
    Language English
    Publishing date 2019-08-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2019.07.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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