TEL(ETV6)-AML1(RUNX1) Initiates Self-renewing Fetal Pro-B Cells in Association with a Transcriptional Program Shared with Embryonic Stem Cells in Mice.
TEL(ETV6)-AML1(RUNX1) Initiates Self-renewing Fetal Pro-B Cells in Association with a Transcriptional Program Shared with Embryonic Stem Cells in Mice.
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TEL(ETV6)-AML1(RUNX1) 启动胎儿 Pro-B 细胞的自我更新，并与小鼠胚胎干细胞共享的转录程序相关。
DOI：
10.1002/stem.1277
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发表时间：
2013
期刊：
影响因子：
5.2
通讯作者：
Tsuzuki S and Seto M.
中科院分区：
文献类型：
--
作者：
Komatsu S;Miyazawa K;Moriya S;Takase A;Naito M;Inazu M;Kohno N;Itoh M;Tomoda A;Tsuzuki S and Seto M.
摘要急性白血病发病机制的最初步骤尚不清楚。TEL-AML 1融合基因通常在出生前产生，产生一个持续的和隐蔽的白血病前克隆，在继发性遗传“命中”积累后可能转化为前体B细胞白血病。在这里，我们表明TEL-AML 1可以诱导小鼠持续自我更新的pro-B细胞。然而，TEL-AML 1+细胞在长期内终末分化，提供了一个“窗口”期，可能允许二次遗传命中积累并导致白血病。TEL-AML 1介导的自我更新与胚胎干细胞（ESC）共享的转录程序相关，其中Mybl 2、Tgif 2、Pim 2和Hmgb 3是建立自我更新pro-B细胞的关键和足够的组分。我们进一步表明，TEL-AML 1增加了白血病起始细胞的数量，这些细胞是与额外的遗传命中合作产生的，从而为开发针对TEL-AML 1相关转录程序的新型治疗和预防措施提供了总体基础。
AbstractThe initial steps involved in the pathogenesis of acute leukemia are poorly understood. TheTEL-AML1fusion gene usually arises before birth, producing a persistent and covert preleukemic clone that may convert to precursor B cell leukemia following the accumulation of secondary genetic “hits.” Here, we show that TEL-AML1 can induce persistent self-renewing pro-B cells in mice. TEL-AML1+ cells nevertheless differentiate terminally in the long term, providing a “window” period that may allow secondary genetic hits to accumulate and lead to leukemia. TEL-AML1-mediated self-renewal is associated with a transcriptional program shared with embryonic stem cells (ESCs), within which Mybl2, Tgif2, Pim2, and Hmgb3 are critical and sufficient components to establish self-renewing pro-B cells. We further show that TEL-AML1 increases the number of leukemia-initiating cells that are generated in collaboration with additional genetic hits, thus providing an overall basis for the development of novel therapeutic and preventive measures targeting the TEL-AML1-associated transcriptional program.