contribution of an aged microenvironment to aging-associated myeloproliferative disease年龄在微环境的贡献aging-associated骨髓增殖性疾病.pdf

Contribution of an Aged Microenvironment to Aging- Associated Myeloproliferative Disease 1 1 ¨ 1 1 1,2 Virag Vas , Corinna Wandhoff , Karin Dorr , Anja Niebel , Hartmut Geiger * 1 Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany, 2 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America Abstract The molecular and cellular mechanisms of the age-associated increase in the incidence of acute myeloid leukemia (AML) remain poorly understood. Multiple studies support that the bone marrow (BM) microenvironment has an important influence on leukemia progression. Given that the BM niche itself undergoes extensive functional changes during lifetime, we hypothesized that one mechanism for the age-associated increase in leukemia incidence might be that an aged niche promotes leukemia progression. The most frequent genetic alteration in AML is the t(8;21) translocation, resulting in the expression of the AML1-ETO fusion protein. Expression of the fusion protein in hematopoietic cells results in mice in a myeloproliferative disorder. Testing the role of the age of the niche on leukemia progression, we performed both transplantation and in vitro co-culture experiments. Aged animals transplanted with AML1-ETO positive HSCs presented with a significant increase in the frequency of AML-ETO positive early progenitor cells in BM as well as an increased immature myeloid cell load in blood compared to young recipients. These findings suggest that an aged BM