Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Division of Molecular Hematology, Lund University, Lund, Sweden.
Adv Exp Med Biol. 2024;1459:143-156. doi: 10.1007/978-3-031-62731-6_7.
The development of highly specialized blood cells from hematopoietic stem cells (HSCs) in the bone marrow (BM) is dependent upon a stringently orchestrated network of stage- and lineage-restricted transcription factors (TFs). Thus, the same stem cell can give rise to various types of differentiated blood cells. One of the key regulators of B-lymphocyte development is early B-cell factor 1 (EBF1). This TF belongs to a small, but evolutionary conserved, family of proteins that harbor a Zn-coordinating motif and an IPT/TIG (immunoglobulin-like, plexins, transcription factors/transcription factor immunoglobulin) domain, creating a unique DNA-binding domain (DBD). EBF proteins play critical roles in diverse developmental processes, including body segmentation in the Drosophila melanogaster embryo, and retina formation in mice. While several EBF family members are expressed in neuronal cells, adipocytes, and BM stroma cells, only B-lymphoid cells express EBF1. In the absence of EBF1, hematopoietic progenitor cells (HPCs) fail to activate the B-lineage program. This has been attributed to the ability of EBF1 to act as a pioneering factor with the ability to remodel chromatin, thereby creating a B-lymphoid-specific epigenetic landscape. Conditional inactivation of the Ebf1 gene in B-lineage cells has revealed additional functions of this protein in relation to the control of proliferation and apoptosis. This may explain why EBF1 is frequently targeted by mutations in human leukemia cases. This chapter provides an overview of the biochemical and functional properties of the EBF family proteins, with a focus on the roles of EBF1 in normal and malignant B-lymphocyte development.
骨髓（BM）中的造血干细胞（HSCs）分化为高度特化的血细胞依赖于严格协调的阶段和谱系限定转录因子（TFs）网络。因此，同一个干细胞可以产生各种类型的分化血细胞。B 淋巴细胞发育的一个关键调节因子是早期 B 细胞因子 1（EBF1）。这种 TF 属于一个小的但进化上保守的蛋白质家族，该家族的蛋白质具有 Zn 配位基序和 IPT/TIG（免疫球蛋白样、多聚蛋白、转录因子/转录因子免疫球蛋白）结构域，形成独特的 DNA 结合结构域（DBD）。EBF 蛋白在多种发育过程中发挥着关键作用，包括果蝇胚胎的体节形成，以及小鼠的视网膜形成。虽然有几个 EBF 家族成员在神经元细胞、脂肪细胞和 BM 基质细胞中表达，但只有 B 淋巴细胞表达 EBF1。在缺乏 EBF1 的情况下，造血祖细胞（HPCs）无法激活 B 细胞谱系程序。这归因于 EBF1 作为一种先驱因子的能力，能够重塑染色质，从而创建 B 淋巴细胞特异性的表观遗传景观。在 B 细胞谱系细胞中条件性失活 Ebf1 基因，揭示了该蛋白在控制增殖和凋亡方面的其他功能。这可能解释了为什么 EBF1 经常成为人类白血病病例中突变的靶点。本章概述了 EBF 家族蛋白的生化和功能特性，重点介绍了 EBF1 在正常和恶性 B 淋巴细胞发育中的作用。
