Runx1 is essential at two stages of early murine B-cell development
Runx1 is essential at two stages of early murine B-cell development
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DOI：
10.1182/blood-2013-01-480244
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发表时间：
2013-07-18
期刊：
影响因子：
20.3
通讯作者：
Stocking, Carol
中科院分区：
文献类型：
--
作者：
Niebuhr, Birte;Kriebitzsch, Neele;Stocking, Carol
t(12;21) 染色体易位是针对编码 RUNX1 转录因子的基因，在 25% 的儿童急性淋巴细胞白血病 (ALL) 中观察到，并且是该疾病的始发事件。为了阐明 RUNX1 破坏引发白血病发生的机制，我们研究了它在小鼠 B 细胞发育中的正常作用。这项研究揭示了 Runx1 的 2 个关键功能：(1) 促进 B 细胞谱系特异祖细胞的存活和发育，这一功能可以被异位 Bcl2 表达替代；(2) 使前 B 细胞抗原受体 (pre-BCR) 触发的前 B 阶段的发育过渡成为可能。基因表达分析和全基因组 Runx1 占用研究支持这样的假设：Runx1 增强了控制早期 B 细胞存活和发育的转录因子网络，并特异性调节编码 Lyn 激酶亚家族成员（白细胞介素 7 和前 BCR 信号传导的关键整合因子）和阶段特异性转录因子 SpiB 和 Aiolos（前 BCR 信号传导的关键下游效应因子）成员的基因。对 257 个 ALL 样本的表达数据库的询问表明，t(12;21) ALL 中 SPIB 和 IKZF3 基因（后者编码 AIOLOS）的特异性下调，为易位阻止 B 细胞发育和促进白血病的机制提供了新的见解。
The t(12;21) chromosomal translocation, targeting the gene encoding the RUNX1 transcription factor, is observed in 25% of pediatric acute lymphoblastic leukemia (ALL) and is an initiating event in the disease. To elucidate the mechanism by which RUNX1 disruption initiates leukemogenesis, we investigated its normal role in murine B-cell development. This study revealed 2 critical functions of Runx1: (1) to promote survival and development of progenitors specified to the B-cell lineage, a function that can be substituted by ectopic Bcl2 expression, and (2) to enable the developmental transition through the pre-B stage triggered by the pre-B-cell antigen receptor (pre-BCR). Gene expression analysis and genomewide Runx1 occupancy studies support the hypothesis that Runx1 reinforces the transcription factor network governing early B-cell survival and development and specifically regulates genes encoding members of the Lyn kinase subfamily (key integrators of interleukin-7 and pre-BCR signaling) and the stage-specific transcription factors SpiB and Aiolos (critical downstream effectors of pre-BCR signaling). Interrogation of expression databases of 257 ALL samples demonstrated the specific down-regulation of the SPIB and IKZF3 genes (the latter encoding AIOLOS) in t(12;21) ALL, providing novel insight into the mechanism by which the translocation blocks B-cell development and promotes leukemia.