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Concomitant inactivation of Rb and E2f8 in hematopoietic stem cells synergizes to induce severe anemia.

Abstract：

:The retinoblastoma (Rb) tumor suppressor plays important roles in regulating hematopoiesis, particularly erythropoiesis. In an effort to understand whether Rb function can be mediated by E2F transcription factors in a BM-derived hematopoietic system in mice, we uncovered a functional synergy between Rb and E2F8 to promote erythropoiesis and to prevent anemia. Specifically, whereas Mx1-Cre-mediated inactivation of Rb or E2f8 in hematopoietic stem cells only led to mild erythropoietic defects, concomitant inactivation of both genes resulted in marked ineffective erythropoiesis and mild hemolysis, leading to severe anemia despite the presence of enhanced extramedullary erythropoiesis. Interestingly, although ineffective erythropoiesis was already present in the RbΔ/Δ mice and exacerbated in the RbΔ/Δ;E2f8Δ/Δ mice, hemolysis was exclusively manifested in the double-knockout mice. Using an adoptive transfer system and an erythroid-specific knockout system, we have shown that the synergy of Rb and E2f8 deficiency in triggering severe anemia is intrinsic to the erythroid lineage. Surprisingly, concomitant inactivation of Rb and E2f7, a close family member of E2f8, did not substantially worsen the erythropoietic defect resulted from Rb deficiency. The results of the present study reveal the specificity of E2F8 in mediating Rb function in erythropoiesis and suggest critical and overlapping roles of Rb and E2f8 in maintaining normal erythropoiesis and in preventing hemolysis.

journal_name

Blood

journal_title

Blood

authors

Hu T,Ghazaryan S,Sy C,Wiedmeyer C,Chang V,Wu L

doi

10.1182/blood-2011-10-388231

subject

Has Abstract

pub_date

2012-05-10 00:00:00

pages

4532-42

issue

19

eissn

0006-4971

issn

1528-0020

pii

blood-2011-10-388231

journal_volume

119

pub_type

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