title: CD45 phosphatase is crucial for human and murine acute myeloid leukemia maintenance through its localization in lipid rafts.
abstract: CD45 is a pan-leukocyte protein with tyrosine phosphatase activity involved in the regulation of signal transduction in hematopoiesis. Exploiting CD45 KO mice and lentiviral shRNA, we prove the crucial role that CD45 plays in acute myeloid leukemia (AML) development and maintenance. We discovered that CD45 does not colocalize with lipid rafts on murine and human non-transformed hematopoietic cells. Using a mouse model, we proved that CD45 positioning within lipid rafts is modified during their oncogenic transformation to AML. CD45 colocalized with lipid rafts on AML cells, which contributes to elevated GM-CSF signal intensity involved in proliferation of leukemic cells. We furthermore proved that the GM-CSF/Lyn/Stat3 pathway that contributes to growth of leukemic cells could be profoundly affected, by using a new plasma membrane disrupting agent, which rapidly delocalized CD45 away from lipid rafts. We provide evidence that this mechanism is also effective on human primary AML samples and xenograft transplantation. In conclusion, this study highlights the emerging evidence of the involvement of lipid rafts in oncogenic development of AML and the targeting of CD45 positioning among lipid rafts as a new strategy in the treatment of AML.
authors: Inserm UMR866, Université Bourgogne-Franche-Comté, Dijon, France.|LipSTIC Labex, Dijon, France.
authors: Laetitia
authors: L
authors: Saint-Paul
authors: Institut Curie, PSL Research University, UMR9187-U1196, CNRS-Institut Curie, Inserm, Centre Universitaire, Orsay, France.
authors: Chi-Hung
authors: CH
authors: Nguyen
authors: Inserm UMR866, Université Bourgogne-Franche-Comté, Dijon, France.|LipSTIC Labex, Dijon, France.
authors: Anne
authors: A
authors: Buffière
authors: LipSTIC Labex, Dijon, France.|Plateforme de lipidomique, Université Bourgogne-Franche-Comté, Dijon, France.
authors: Jean-Paul
authors: JP
authors: Pais de Barros
authors: Plateforme de cytométrie, Université Bourgogne-Franche-Comté, Dijon, France.
authors: Arlette
authors: A
authors: Hammann
authors: Institut Curie, PSL Research University, UMR9187-U1196, CNRS-Institut Curie, Inserm, Centre Universitaire, Orsay, France.
authors: Corinne
authors: C
authors: Landras-Guetta
authors: INRA, UMR1324, Dijon, France.
authors: Rodolphe
authors: R
authors: Filomenko
authors: Inserm UMR866, Université Bourgogne-Franche-Comté, Dijon, France.|LipSTIC Labex, Dijon, France.|Hôpital Universitaire François-Mitterrand, Service d'Hématologie Clinique, Dijon, France.
authors: Marie-Lorraine
authors: ML
authors: Chrétien
authors: Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Pauline
authors: P
authors: Johnson
authors: Inserm UMR866, Université Bourgogne-Franche-Comté, Dijon, France.|LipSTIC Labex, Dijon, France.|Hôpital Universitaire François-Mitterrand, Service d'Hématologie Clinique, Dijon, France.
authors: Jean-Noël
authors: JN
authors: Bastie
authors: Inserm UMR866, Université Bourgogne-Franche-Comté, Dijon, France.|LipSTIC Labex, Dijon, France.
authors: Laurent
authors: L
authors: Delva
authors: Inserm UMR866, Université Bourgogne-Franche-Comté, Dijon, France.|LipSTIC Labex, Dijon, France.
authors: Ronan
authors: R
authors: Quéré
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human
keywords: CD45 phosphatase; acute myeloid leukemia; hematopoietic cells; lipid rafts; oncogenic transformation