title: Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice.
abstract: Loss of immune function and increased hematopoietic disease are among the most clinically significant consequences of aging. Hematopoietic stem cells (HSCs) from mice lacking aryl hydrocarbon receptor (AhR) have high rates of cell division. Studies were designed to test the hypothesis that aging AhR-null allele (AhR-KO) mice develop premature HSC exhaustion, and changes leading to hematological disease. Compared to wild-type, aging AhR-KO mice showed a decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, and anemia. Analysis of bone marrow indicated increased numbers of stem/progenitor and lineage-committed cells, but decreased erythroid progenitors. There was also decreased self-renewal capacity of HSCs determined by competitive repopulation and serial transplantation. HSCs also showed increased levels of reactive oxygen species (ROS), Ki-67, and γ-H2A.X, but decreased p16(Ink4a). Splenic cells from aging KO mice had abnormal expression of genes, including Gata-1, Sh2d3c, Gfi-1, p21, and c-myc, involved in trafficking and associated with leukemia. HSCs from AhR-KO mice had gene changes related to HSC maintenance and consistent with phenotype observed. The most prominent gene changes (overexpression of Srpk2, Creb1, Hes1, mtor, pdp1) have been associated with HSC hyperproliferation, leukemia, and accelerated aging. Pathway analyses also indicated an enrichment of genes associated with oxidative stress, acute myelogenous leukemia, aging, and heat shock response, and the β-catenin/Wnt pathways. These data indicate that loss of AhR and associated changes in multiple signaling pathways promote premature HSC exhaustion and development of a myeloproliferative disorder. They also implicate a critical role of the AhR in the regulation of HSCs.
authors.affiliation: 1 Department of Environmental Medicine, University of Rochester School of Medicine , Rochester, New York.
authors.forename: Kameshwar P
authors.initials: KP
authors.lastname: Singh
authors.forename: John A
authors.initials: JA
authors.lastname: Bennett
authors.forename: Fanny L
authors.initials: FL
authors.lastname: Casado
authors.forename: Jason L
authors.initials: JL
authors.lastname: Walrath
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Welle
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gasiewicz
mesh_terms: D000375:Aging / Q000235:genetics* / Q000276:immunology*; D000740:Anemia / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001854:Bone Marrow Cells / Q000166:cytology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006657:Histones / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013163:Splenomegaly / Q000235:genetics; D015996:Survival Rate
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D019394:Ki-67 Antigen; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C498355:Mki67 protein, mouse; C475961:gamma-H2AX protein, mouse