Blood：Rb及E2f8能够协同作用于造血作用

近日，美国新泽西医科和牙科大学的研究人员发现，造血干细胞内Rb及E2f8的联合失活协同导致了严重贫血的发生。

之前的研究表明，视网膜母细胞瘤(Rb)抑癌基因对造血功能的调节具有重要作用。在老鼠的一个骨髓（BM）衍生的造血系统，为了研究RB的功能是否能被转录因子E2F所介导，他们意外的发现Rb及E2f8能够协同作用，共同促进红细胞形成并预防贫血发生。

然而在造血干细胞，Mx1-Cre–介导了Rb或者E2f8的失活，仅仅导致了轻微的红血球生成缺陷。但是这两种基因联合失活后，尽管存在增强的髓外红细胞形成作用，仍然会导致无效的红血球生成及轻微的溶血现象，引起了严重贫血的发生。

有趣的是，虽然无效性红细胞生成已经在Rb^Δ/Δ小鼠体内发生，并在Rb^Δ/Δ;E2f8^Δ/Δ小鼠内恶化，这种溶血现象都是专一的出现在双敲除的小鼠。

利用一个过继转化系统以及红细胞特异的敲除系统，研究人员发现，Rb及E2f8的缺陷协同促进了红细胞相关的严重贫血。

E2f7是E2f8相近的家族成员，研究发现，Rb及E2f7的联合失活不会引起恶化的红细胞生成的缺陷。

总的来说，该研究表明，E2F8能够特异性的介导Rb作用于红细胞的生成。这表明在维持正常的红细胞生成及预防贫血时，Rb及E2f8的作用是严格而且是重叠的。

doi: 10.1182/blood-2011-10-388231
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Concomitant inactivation of Rb and E2f8 in hematopoietic stem cells synergizes to induce severe anemia

Tinghui Hu, Seda Ghazaryan, Chandler Sy, Charles Wiedmeyer, Victor Chang, and Lizhao Wu1.

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.