Herblot Sabine, Aplan Peter D, Hoang Trang
The Clinical Research Institute of Montréal, Montréal, Québec, Canada.
Mol Cell Biol. 2002 Feb;22(3):886-900. doi: 10.1128/MCB.22.3.886-900.2002.
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/Tal1, 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.
E2A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。E2A编码两种产物,E12和E47,它们是转录因子基本螺旋-环-螺旋(bHLH)家族的一部分,在B细胞谱系分化中起核心作用。E2A单倍体不足阻碍了B细胞发育过程中的三个主要检查点:进入B细胞谱系、从前B细胞到前B细胞的转变以及功能性BCR所需的免疫球蛋白M(IgM)表达的诱导。这些观察结果强调了E2A基因剂量在B细胞发育中的重要性。在这里,我们表明,与野生型同窝小鼠相比,E2A(+/-)小鼠中处于细胞周期的前B细胞比例更高。这种增加与较低的p21(waf/cip1)水平相关,表明E2A在B细胞祖细胞中具有抗增殖功能。在B细胞谱系中异位表达抑制E2A功能的组织特异性bHLH因子SCL/Tal1,会阻断进入B细胞谱系,而不影响分化后期的进程。此外,异位SCL表达会加剧B细胞分化中E2A单倍体不足,表明SCL与E2A存在遗传相互作用。综上所述,这些观察结果为从前前B细胞到前B细胞阶段E2A活性逐渐增加的梯度提供了证据,并提出了一个模型,即低水平的E2A(如在前B细胞中)足以控制细胞生长,而高水平(在前B细胞中)是细胞分化所必需的。E2A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E2A融合蛋白诱导的其他异常外,一个E2A等位基因的破坏也有助于白血病的发生。