Gradient of E2A activity in B-cell development
Gradient of E2A activity in B-cell development
复制标题
DOI：
10.1128/mcb.22.3.886-900.2002
复制
发表时间：
2002-02-01
影响因子：
5.3
通讯作者：
Hoang, T
中科院分区：
文献类型：
--
作者：
Herblot, S;Aplan, PD;Hoang, T
E2 A基因座是B细胞急性淋巴细胞白血病（B-ALL）中染色体易位的常见靶点。E2 A编码两种产物E12和E47，它们是转录因子的基本螺旋-环-螺旋（bHLH）家族的一部分，并且在B谱系分化中是中心的。E2 A单倍体不足通过B细胞发育中的三个主要检查点阻碍进展：定型为B谱系、前B向前B的转变以及诱导功能性BCR所需的免疫球蛋白M（IgM）表达。这些观察结果强调了E2 A基因剂量在B细胞发育中的重要性。在这里，我们表明，在E2 A（+/-）小鼠中的pro-B细胞的比例较高，在细胞周期中相比，在野生型同窝仔。这种增加与较低的P21（waf/cip 1）水平相关，表明E2 A在B细胞祖细胞中具有抗增殖功能。SCL/Tall（一种抑制E2 A功能的组织特异性bHLH因子）在B谱系中的异位表达阻断了向B谱系的定型，而不影响后期分化阶段的进展。此外，异位SCL表达加剧了E2 A单倍不足的B细胞分化，表明SCL与E2 A的遗传相互作用。综上所述，这些观察结果提供了E2 A活性梯度的证据，该梯度从前原B阶段到前B阶段增加，并提出了一种模型，其中低水平的E2 A（如在原B细胞中）足以控制细胞生长，而高水平的E2 A（在前B细胞中）是细胞分化所需的。E2 A的抗增殖功能进一步表明，在与t（1;19）和t（17;19）相关的B-ALL中，除了E2 A融合蛋白诱导的其他异常外，一个E2 A等位基因的破坏有助于白血病发生。
The E2A locus is a frequent target of chromosomal translocations in B-cell acute lymphoblastic leukemia (B-ALL). E2A encodes two products, E12 and E47, that are part of the basic helix-loop-helix (bHLH) family of transcription factors and are central in B lineage differentiation. E2A haplo-insufficiency hinders progression through three major checkpoints in B-cell development: commitment into the B lineage, at the pro-B to pre-B transition, and in the induction of immunoglobulin M (IgM) expression required for a functional BCR. These observations underscore the importance of E2A gene dosage in B-cell development. Here we show that a higher proportion of pro-B cells in E2A(+/-) mice is in the cell cycle compared to that in wild-type littermates. This increase correlates with lower P21(waf/cip1) levels, indicating that E2A has an antiproliferative function in B-cell progenitors. Ectopic expression in the B lineage of SCL/Tall, a tissue-specific bHLH factor that inhibits E2A function, blocks commitment into the B lineage without affecting progression through later stages of differentiation. Furthermore, ectopic SCL expression exacerbates E2A haplo-insufficiency in B-cell differentiation, indicating that SCL genetically interacts with E2A. Taken together, these observations provide evidence for a gradient of E2A activity that increases from the pre-pro-B to the pre-B stage and suggest a model in which low levels of E2A (as in pro-B cells) are sufficient to control cell growth, while high levels (in pre-B cells) are required for cell differentiation. The antiproliferative function of E2A further suggests that in B-ALL associated with t(1;19) and t(17;19), the disruption of one E2A allele contributes to leukemogenesis, in addition to other anomalies induced by E2A fusion proteins.