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PLCG1 is required for AML1-ETO leukemia stem cell self-renewal.
Schnoeder, Tina M; Schwarzer, Adrian; Jayavelu, Ashok Kumar; Hsu, Chen-Jen; Kirkpatrick, Joanna; Döhner, Konstanze; Perner, Florian; Eifert, Theresa; Huber, Nicolas; Arreba-Tutusaus, Patricia; Dolnik, Anna; Assi, Salam A; Nafria, Monica; Jiang, Lu; Dai, Yu-Ting; Chen, Zhu; Chen, Sai-Juan; Kellaway, Sophie G; Ptasinska, Anetta; Ng, Elizabeth S; Stanley, Edouard G; Elefanty, Andrew G; Buschbeck, Marcus; Bierhoff, Holger; Brodt, Steffen; Matziolis, Georg; Fischer, Klaus-Dieter; Hochhaus, Andreas; Chen, Chun-Wei; Heidenreich, Olaf; Mann, Matthias; Lane, Steven W; Bullinger, Lars; Ori, Alessandro; von Eyss, Björn; Bonifer, Constanze; Heidel, Florian H.
  • Schnoeder TM; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.
  • Schwarzer A; Department of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, and.
  • Jayavelu AK; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
  • Hsu CJ; Max-Planck-Institute of Biochemistry, Munich, Germany.
  • Kirkpatrick J; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.
  • Döhner K; Leibniz Institute on Aging, Fritz-Lipmann Institute (FLI), Jena, Germany.
  • Perner F; Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
  • Eifert T; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.
  • Huber N; Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard University, Boston, MA.
  • Arreba-Tutusaus P; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.
  • Dolnik A; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.
  • Assi SA; Department of Oncology, Hematology, Immunology, and Rheumatology, University Hospital Tübingen, Tübingen, Germany.
  • Nafria M; Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany.
  • Jiang L; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Dai YT; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Chen Z; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Chen SJ; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Kellaway SG; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Ptasinska A; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Ng ES; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Stanley EG; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Elefanty AG; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
  • Buschbeck M; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
  • Bierhoff H; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne Parkville, VIC, Australia.
  • Brodt S; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
  • Matziolis G; Josep Carreras Leukemia Research Institute, Badalona, Spain.
  • Fischer KD; Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich-Schiller University, Jena, Germany.
  • Hochhaus A; University Hospital Jena, Orthopaedic Department at Campus Eisenberg, Eisenberg, Germany.
  • Chen CW; University Hospital Jena, Orthopaedic Department at Campus Eisenberg, Eisenberg, Germany.
  • Heidenreich O; Institute for Cell Biology and Biochemistry, Otto-von-Guericke University, Magdeburg, Germany.
  • Mann M; Innere Medizin 2, Hämatologie und Onkologie, Universitätsklinikum Jena, Germany.
  • Lane SW; Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA.
  • Bullinger L; Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, United Kingdom.
  • Ori A; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; and.
  • von Eyss B; Max-Planck-Institute of Biochemistry, Munich, Germany.
  • Bonifer C; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
  • Heidel FH; Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany.
Blood ; 139(7): 1080-1097, 2022 02 17.
Article en En | MEDLINE | ID: mdl-34695195
ABSTRACT
In an effort to identify novel drugs targeting fusion-oncogene-induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE)-driven AML, we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein that is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO+ leukemic stem cells.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Células Madre Hematopoyéticas / Leucemia Mieloide Aguda / Regulación Leucémica de la Expresión Génica / Proteínas de Fusión Oncogénica / Fosfolipasa C gamma / Subunidad alfa 2 del Factor de Unión al Sitio Principal / Proteína 1 Compañera de Translocación de RUNX1 Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2022 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Células Madre Hematopoyéticas / Leucemia Mieloide Aguda / Regulación Leucémica de la Expresión Génica / Proteínas de Fusión Oncogénica / Fosfolipasa C gamma / Subunidad alfa 2 del Factor de Unión al Sitio Principal / Proteína 1 Compañera de Translocación de RUNX1 Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2022 Tipo del documento: Article