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CD45 phosphatase is crucial for human and murine acute myeloid leukemia maintenance through its localization in lipid rafts

2016; Impact Journals LLC; Volume: 7; Issue: 40 Linguagem: Inglês

10.18632/oncotarget.11622

1949-2553

Laetitia Saint-Paul, Chi-Hung Nguyen, Anne Buffière, Jean-Paul Paı̈s de Barros, Arlette Hammann, Corinne Landras-Guetta, Rodolphe Filomenko, Marie‐Lorraine Chrétien, Pauline Johnson, Jean Bastié, Laurent Delva, Ronan Quéré,

RNA Interference and Gene Delivery

// Laetitia Saint-Paul 1,2 , Chi-Hung Nguyen 3 , Anne Buffière 1,2 , Jean-Paul Pais de Barros 2,4 , Arlette Hammann 5 , Corinne Landras-Guetta 3 , Rodolphe Filomenko 6 , Marie-Lorraine Chrétien 1,2,7 , Pauline Johnson 8 , Jean-Noël Bastie 1,2,7 , Laurent Delva 1,2 and Ronan Quéré 1,2 1 Inserm UMR866, Université Bourgogne-Franche-Comté, Dijon, France 2 LipSTIC Labex, Dijon, France 3 Institut Curie, PSL Research University, UMR9187–U1196, CNRS-Institut Curie, Inserm, Centre Universitaire, Orsay, France 4 Plateforme de lipidomique, Université Bourgogne-Franche-Comté, Dijon, France 5 Plateforme de cytométrie, Université Bourgogne-Franche-Comté, Dijon, France 6 INRA, UMR1324, Dijon, France 7 Hôpital Universitaire François-Mitterrand, Service d'Hématologie Clinique, Dijon, France 8 Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada Correspondence to: Ronan Quéré, email: // Keywords : acute myeloid leukemia, CD45 phosphatase, lipid rafts, hematopoietic cells, oncogenic transformation Received : July 20, 2016 Accepted : August 20, 2016 Published : August 25, 2016 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.