RRC ID 53215
Author Ikeda K, Ueda T, Yamasaki N, Nakata Y, Sera Y, Nagamachi A, Miyama T, Kobayashi H, Takubo K, Kanai A, Oda H, Wolff L, Honda Z, Ichinohe T, Matsubara A, Suda T, Inaba T, Honda H.
Title Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency.
Journal Sci Rep
Abstract Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (Eed(Δ/Δ)) mice. Eed(Δ/Δ) mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in Eed(Δ/Δ) HSPCs, and consistently, Eed(Δ/Δ) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Δ/Δ) HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis.
Volume 6
Pages 29454
Published 2016-7-19
DOI 10.1038/srep29454
PII srep29454
PMID 27432459
PMC PMC4949429
MeSH Animals Antigens, CD34 / metabolism Cell Adhesion Cell Cycle Cell Differentiation Cell Proliferation Cell Transformation, Neoplastic Extracellular Matrix / metabolism Female Fetal Blood / cytology Fibronectins / chemistry Fibronectins / metabolism Flow Cytometry Gene Transfer Techniques Haploinsufficiency* Hematologic Neoplasms / genetics Hematologic Neoplasms / metabolism Hematopoiesis* Hematopoietic Stem Cells / cytology Heterozygote Histones Leukemia / genetics Leukemia / metabolism* Male Mice Mice, Inbred C57BL Polycomb Repressive Complex 2 / genetics* Polycomb Repressive Complex 2 / physiology* RNA, Small Interfering / metabolism
IF 3.998
Times Cited 5
Cord blood stem cells for research