Cbfb‐SMMHC impairs differentiation of Common Lymphoid Progenitors and reveals an essential role for RUNX in early B cell development
Cbfb‐SMMHC impairs differentiation of Common Lymphoid Progenitors and reveals an essential role for RUNX in early B cell development
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Cbfb-SMMHC 损害共同淋巴祖细胞的分化并揭示 RUNX 在早期 B 细胞发育中的重要作用
DOI：
10.1096/fasebj.22.1_supplement.842.9
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
L. Castilla
中科院分区：
文献类型：
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作者：
R. Gerstein;Ya;L. Castilla
核心结合因子（CBF）相关白血病融合蛋白 CBFβ-SMMHC 损害骨髓和淋巴分化。通过抑制 RUNX 功能，融合癌蛋白在患者和小鼠模型中特异性地诱发急性髓系白血病。我们已经证明，Cbfβ-SMMHC 表达会导致小鼠循环 B 淋巴细胞持续减少。在这项研究中，我们证明 Cbfβ-SMMHC 的激活使前原 B 细胞和原 B 细胞减少约 3 倍，前 B 细胞减少超过 10 倍，并且这种分化块是细胞自主的。前 B 细胞前体的减少与该群体细胞凋亡的增加同时发生。共同淋巴祖细胞 (CLP) 的数量未受影响，但 CLP 中关键早期 B 细胞因子 Ebf1、Tcfe2a 和 Pax5 的表达显着降低。此外，Cbfβ-SMMHC 降低了 Rag1 和 Rag2 的表达，并损害了 CLP 中的 V(D)J 重组。此外，表达 Cbfβ-SMMHC 的 CLP 还表现出对 B 细胞特异性基因 Cd79a、Igll1、VpreB1 和 Blk 的抑制。这些结果表明，CBF/RUNX 功能对于 CLP 的功能、前 B 细胞的存活和分化以及 B 谱系特异性转录程序的建立至关重要。
The core‐binding factor (CBF)‐associated leukemia fusion protein CBFβ‐SMMHC impairs myeloid and lymphoid differentiation. By inhibiting RUNX function, the fusion oncoprotein predisposes specifically to acute myeloid leukemia in both patients and mouse models. We have shown that Cbfβ‐SMMHC expression leads to a sustained reduction of circulating B lymphocytes in the mouse. In this study, we demonstrate that the activation of Cbfβ‐SMMHC reduces both pre‐pro‐B and pro‐ B cells approximately 3 fold, pre‐B cells over 10 fold and that this differentiation block is cell‐autonomous. The reduction of pre‐pro‐B cells coincided with an increase in apoptosis in this population. The number of common lymphoid progenitors (CLPs) were not affected, however, the expression of critical early B cell factors Ebf1, Tcfe2a, and Pax5 in CLPs were significantly reduced. In addition, Cbfβ‐SMMHC reduced Rag1 and Rag2 expression, and impaired V(D)J recombination in the CLPs. Furthermore, CLPs expressing Cbfβ‐SMMHC also show inhibition of B cell‐specific genes Cd79a, Igll1, VpreB1 and Blk. These results demonstrate that CBF/RUNX function is essential for the function of CLPs, the survival and differentiation of pre‐pro‐B cells, and the establishment of a B lineage‐specific transcriptional program.