Runx1 and Cbfβ regulate the development of Flt3+ dendritic cell progenitors and restrict myeloproliferative disorder
Runx1 and Cbfβ regulate the development of Flt3+ dendritic cell progenitors and restrict myeloproliferative disorder
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DOI：
10.1182/blood-2013-11-539643
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发表时间：
2014-05-08
期刊：
影响因子：
20.3
通讯作者：
Egawa, Takeshi
中科院分区：
文献类型：
--
作者：
Satpathy, Ansuman T.;Briseno, Carlos G.;Egawa, Takeshi
RUNX1和CBFβ对于确定的造血系统的建立至关重要，并与白血病的转化有关。尽管在造血干细胞和淋巴细胞的发育中对这些因子有绝对的要求，但它们在骨髓祖细胞亚群发育中的作用尚未确定。在这里，我们证明了CBFβ对于骨髓和外周所有DC亚群中的Flt3(+)巨噬细胞-树突状细胞(DC)前体细胞的发育是必不可少的。除了DC祖细胞的丧失外，泛造血型CBFβ缺陷小鼠也缺乏CD105(+)红系祖细胞，导致3至4个月大的严重贫血。相反，CBFβ缺乏导致祖细胞向粒-巨噬细胞祖细胞(GMPs)异常分化，导致骨髓增殖性表型，GMPs聚集在外周和肝脏的细胞浸润。在CBFβ缺陷的祖细胞中，转录因子IRF8的表达严重降低，而IRF8的过表达恢复了DC的分化。这些结果表明，RUNX蛋白和CBFβ限制粒细胞系的承诺，以促进多系造血分化，从而确定它们在髓系白血病中的新的肿瘤抑制功能。
Runx1 and Cbf beta are critical for the establishment of definitive hematopoiesis and are implicated in leukemic transformation. Despite the absolute requirements for these factors in the development of hematopoietic stem cells and lymphocytes, their roles in the development of bone marrow progenitor subsets have not been defined. Here, we demonstrate that Cbf beta is essential for the development of Flt3(+) macrophage-dendritic cell (DC) progenitors in the bone marrow and all DC subsets in the periphery. Besides the loss of DC progenitors, pan-hematopoietic Cbf beta-deficient mice also lack CD105(+) erythroid progenitors, leading to severe anemia at 3 to 4 months of age. Instead, Cbf beta deficiency results in aberrant progenitor differentiation toward granulocyte-macrophage progenitors (GMPs), resulting in a myeloproliferative phenotype with accumulation of GMPs in the periphery and cellular infiltration of the liver. Expression of the transcription factor Irf8 is severely reduced in Cbf beta-deficient progenitors, and overexpression of Irf8 restors DC differentiation. These results demonstrate that Runx proteins and Cbf beta restrict granulocyte lineage commitment to facilitate multilineage hematopoietic differentiation and thus identify their novel tumor suppressor function in myeloid leukemia.