title: Tet2 disruption leads to enhanced self-renewal and altered differentiation of fetal liver hematopoietic stem cells.
abstract: Somatic mutation of ten-eleven translocation 2 (TET2) gene is frequently found in human myeloid malignancies. Recent reports showed that loss of Tet2 led to pleiotropic hematopoietic abnormalities including increased competitive repopulating capacity of bone marrow (BM) HSCs and myeloid transformation. However, precise impact of Tet2 loss on the function of fetal liver (FL) HSCs has not been examined. Here we show that disruption of Tet2 results in the expansion of Lin(-)Sca-1(+)c-Kit(+) (LSK) cells in FL. Furthermore, Tet2 loss led to enhanced self-renewal and long-term repopulating capacity of FL-HSCs in in vivo serial transplantation assay. Disruption of Tet2 in FL also led to altered differentiation of mature blood cells, expansion of common myeloid progenitors and increased resistance for hematopoietic progenitor cells (HPCs) to differentiation stimuli in vitro. These results demonstrate that Tet2 plays a critical role in homeostasis of HSCs and HPCs not only in the BM, but also in FL.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kunimoto
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fukuchi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Sakurai
authors.forename: Ken
authors.initials: K
authors.lastname: Sadahira
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008099:Liver / Q000166:cytology / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse