title: Contribution of an aged microenvironment to aging-associated myeloproliferative disease.
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 microenvironment allows a relative better expansion of pre-leukemic stem and immature myeloid cells and thus imply that the aged microenvironment plays a role in the elevated incidence of age-associated leukemia.
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
authors.forename: Virag
authors.initials: V
authors.lastname: Vas
authors.forename: Corinna
authors.initials: C
authors.lastname: Wandhoff
authors.forename: Karin
authors.initials: K
authors.lastname: Dörr
authors.forename: Anja
authors.initials: A
authors.lastname: Niebel
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D018450:Disease Progression; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D009196:Myeloproliferative Disorders / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D055153:Stem Cell Niche; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein