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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.
Affiliation
  • Menendez-Gonzalez JB; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Vukovic M; Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
  • Abdelfattah A; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Saleh L; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Almotiri A; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Thomas LA; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Agirre-Lizaso A; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Azevedo A; Department of Hematology, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff CF14 4XW, UK.
  • Menezes AC; Department of Hematology, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff CF14 4XW, UK.
  • Tornillo G; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Edkins S; Wales Gene Park and Wales Cancer Research Centre, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF10 3XQ, UK.
  • Kong K; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
  • Giles P; Wales Gene Park and Wales Cancer Research Centre, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF10 3XQ, UK.
  • Anjos-Afonso F; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK.
  • Tonks A; Department of Hematology, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff CF14 4XW, UK.
  • Boyd AS; Department of Surgical Biotechnology, Division of Surgery and Interventional Science, Royal Free Hospital, University College London, London NW3 2PF, UK; Institute of Immunity and Transplantation, University College London, London NW3 2QG, UK.
  • Kranc KR; Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
  • Rodrigues NP; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK. Electronic address: rodriguesn@cardiff.ac.uk.
Stem Cell Reports ; 13(2): 291-306, 2019 08 13.
Article in En | MEDLINE | ID: mdl-31378673
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Hematopoietic Stem Cells / GATA2 Transcription Factor Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Stem Cell Reports Year: 2019 Type: Article Affiliation country: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Hematopoietic Stem Cells / GATA2 Transcription Factor Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Stem Cell Reports Year: 2019 Type: Article Affiliation country: United kingdom