PLCG1 is required for AML1-ETO leukemia stem cell self-renewal.

Autor:	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.; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany., Jayavelu AK; Max-Planck-Institute of Biochemistry, Munich, Germany., Hsu CJ; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany., Kirkpatrick J; Leibniz Institute on Aging, Fritz-Lipmann Institute (FLI), Jena, Germany., Döhner K; Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany., Perner F; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.; Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard University, Boston, MA., Eifert T; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany., Huber N; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany., Arreba-Tutusaus P; Department of Oncology, Hematology, Immunology, and Rheumatology, University Hospital Tübingen, Tübingen, Germany., Dolnik A; Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany., Assi SA; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom., Nafria M; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom., Jiang L; 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., Dai YT; 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 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; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom., Ptasinska A; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom., Ng ES; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia., Stanley EG; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne Parkville, VIC, Australia., Elefanty AG; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia., Buschbeck M; Josep Carreras Leukemia Research Institute, Badalona, Spain., Bierhoff H; Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich-Schiller University, Jena, Germany., Brodt S; University Hospital Jena, Orthopaedic Department at Campus Eisenberg, Eisenberg, Germany., Matziolis G; University Hospital Jena, Orthopaedic Department at Campus Eisenberg, Eisenberg, Germany., Fischer KD; Institute for Cell Biology and Biochemistry, Otto-von-Guericke University, Magdeburg, Germany., Hochhaus A; Innere Medizin 2, Hämatologie und Onkologie, Universitätsklinikum Jena, Germany., Chen CW; Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA., Heidenreich O; Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, United Kingdom.; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; and., Mann M; Max-Planck-Institute of Biochemistry, Munich, Germany., Lane SW; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Bullinger L; Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany., Ori A; Leibniz Institute on Aging, Fritz-Lipmann Institute (FLI), Jena, Germany., von Eyss B; Leibniz Institute on Aging, Fritz-Lipmann Institute (FLI), Jena, Germany., Bonifer C; Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom., Heidel FH; Innere Medizin C, Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.; Leibniz Institute on Aging, Fritz-Lipmann Institute (FLI), Jena, Germany.; Innere Medizin 2, Hämatologie und Onkologie, Universitätsklinikum Jena, Germany.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Feb 17; Vol. 139 (7), pp. 1080-1097.
DOI:	10.1182/blood.2021012778
Abstrakt:	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. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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