Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency

Kenichiro Ikeda, Takeshi Ueda, Norimasa Yamasaki, Yuichiro Nakata, Yasuyuki Sera, Akiko Nagamachi, Takahiko Miyama, Hiroshi Kobayashi, Keiyo Takubo, Akinori Kanai, Hideaki Oda, Linda Wolff, Zen Ichiro Honda, Tatsuo Ichinohe, Akio Matsubara, Toshio Suda, Toshiya Inaba, Hiroaki Honda

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 "/ ") mice. Eed "/ " 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 "/ " HSPCs, and consistently, Eed "/ " 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 "/ " 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.

Original languageEnglish (US)
Article number29454
JournalScientific reports
Volume6
DOIs
StatePublished - Jul 19 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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