6533b833fe1ef96bd129c8de

RESEARCH PRODUCT

Role of the protein phosphatase CD45 and lipid rafts in the maintenance of acute myeloblastic leukemiaand development of a new therapeutic treatment

subject

description

CD45 is a pan-leukocyte protein with tyrosine phosphatase activity involved in the regulation of cytokinereceptors in hematopoiesis, such as the GM-CSF. We report here on new chemical compound,Pyrido[4,3-b]quinoxaline (PyQ), which is a plasma membrane disrupting agent, as a potential drug fortreatment of acute myeloid leukemia (AML). Indeed, we show that the hematopoietic cell lines aremore sensitive to PyQ, compared with non- hematopoietic cell lines. Using HOXA9-MEIS1-transformed blasts from a mouse model to study AML and human primary AML samples, wediscovered that CD45, which is mainly found within plasma-membrane lipid rafts, is rapidly delocalizedafter treatment with PyQ compound. The localization of CD45 phosphatase within or outside plasmamembranelipid rafts is crucial for dephosphorylation of Src family kinases. Lyn (Src) kinaseconsequently becomes phosphorylated at its inhibitory site, which affects the GM-CSF pathway, a keycytokine that contributes to the growth and survival of leukemic cells and therefore AML maintenance.Blasts expressing high levels of CD45 are enriched in leukemia initiating cells, are more sensitive toPyQ, and exhibit increased GM-CSF signaling. Importantly, CD45 is not found localized within lipidrafts on murine and human non-transformed hematopoietic cells, and reduced toxicity of PyQ istherefore observed in normal primitive hematopoietic cells. Furthermore, when mice are treated invivo, PyQ compound only affects HOXA9-MEIS1- transformed blasts, without disturbing thereconstitution ability of normal primitive hematopoietic cells. In conclusion, we have strengthenedemerging evidence of the involvement of lipid rafts in AML malignancies, and the targeting of lipid raftsas therapy in treatment of AML