Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development.
Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development.
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Mll-AF 4在发育受限窗口期间赋予增强的自我更新和拟人潜力。
DOI：
10.1016/j.celrep.2016.06.046
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发表时间：
2016-07-26
期刊：
影响因子：
8.8
通讯作者：
Ottersbach K
中科院分区：
文献类型：
--
作者：
Barrett NA;Malouf C;Kapeni C;Bacon WA;Giotopoulos G;Jacobsen SEW;Huntly BJ;Ottersbach K
MLL-AF 4+婴儿B细胞急性淋巴细胞白血病的特征是发病早，存活率低。它开始出生前，和很少是已知的疾病的发展的早期阶段。使用有条件的Mll-AF 4表达小鼠模型，其中融合表达的目标是最早的最终造血细胞在小鼠胚胎中产生的，我们证明，Mll-AF 4赋予增强B淋巴潜能，并增加再增殖和自我更新能力在一个假定的前白血病状态。这发生在胚胎的第12和14天之间，并且在淋巴启动的多能祖细胞群体中表现得最强烈，从而指出了机会之窗和潜在的起源细胞。然而，这种状态本身不足以产生疾病，小鼠只有在长时间潜伏后才死于B细胞淋巴瘤。未来对白血病前期状态的分子细节的分析将揭示进展为急性白血病所需的其他事件。MII-AF 4赋予增强的B细胞潜能并引起前B细胞的扩增MII-AF 4增加自我更新潜能MII-AF 4在受限的发育窗口中发挥其作用。描述了由M11-AF 4致癌基因在体内诱导的出生前造血的变化。这些包括增强的B淋巴潜能、前B细胞的扩增和增加的自我更新。作者确定妊娠中期淋巴启动的多能祖细胞为潜在的起源细胞。
MLL-AF4+ infant B cell acute lymphoblastic leukemia is characterized by an early onset and dismal survival. It initiates before birth, and very little is known about the early stages of the disease’s development. Using a conditional Mll-AF4-expressing mouse model in which fusion expression is targeted to the earliest definitive hematopoietic cells generated in the mouse embryo, we demonstrate that Mll-AF4 imparts enhanced B lymphoid potential and increases repopulation and self-renewal capacity during a putative pre-leukemic state. This occurs between embryonic days 12 and 14 and manifests itself most strongly in the lymphoid-primed multipotent progenitor population, thus pointing to a window of opportunity and a potential cell of origin. However, this state alone is insufficient to generate disease, with the mice succumbing to B cell lymphomas only after a long latency. Future analysis of the molecular details of this pre-leukemic state will shed light on additional events required for progression to acute leukemia. Mll-AF4 confers enhanced B cell potential and causes an expansion of pro-B cells Mll-AF4 increases self-renewal potential Mll-AF4 exerts its effects in a restricted developmental window The LMPP is a potential cell of origin for Mll-AF4-associated disease Barrett et al. describe the changes in pre-natal hematopoiesis induced by the Mll-AF4 oncogene in vivo. These include enhanced B lymphoid potential, an expansion of pro-B cells, and increased self-renewal. The authors identify the midgestation lymphoid-primed multipotent progenitor as a potential cell of origin.