Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2312-7. doi: 10.1073/pnas.1212904110. Epub 2013 Jan 23.
Hematopoietic stem cells (HSCs) are the source of all blood lineages, and HSCs must balance quiescence, self-renewal, and differentiation to meet lifelong needs for blood cell development. Transformation of HSCs by the breakpoint cluster region-ABL tyrosine kinase (BCR-ABL) oncogene causes chronic myelogenous leukemia (CML). The E-twenty six (ets) transcription factor GA binding protein (GABP) is a tetrameric transcription factor complex that contains GABPα and GABPβ proteins. Deletion in bone marrow of Gabpa, the gene that encodes the DNA-binding component, caused cell cycle arrest in HSCs and profound loss of hematopoietic progenitor cells. Loss of Gabpα prevented development of CML, although mice continued to generate BCR-ABL-expressing Gabpα-null cells for months that were serially transplantable and contributed to all lineages in secondary recipients. A bioinformatic screen identified the serine-threonine kinase protein kinase D2 (PRKD2) as a potential effector of GABP in HSCs. Prkd2 expression was markedly reduced in Gabpα-null HSCs and progenitor cells. Reduced expression of PRKD2 or pharmacologic inhibition decreased cell cycling, and PRKD2 rescued growth of Gabpα-null BCR-ABL-expressing cells. Thus, GABP is required for HSC cell cycle entry and CML development through its control of PRKD2. This offers a potential therapeutic target in leukemia.
造血干细胞（HSCs）是所有血液谱系的来源，HSCs 必须平衡静止、自我更新和分化，以满足终生对血细胞发育的需求。HSCs 被断点簇区-ABL 酪氨酸激酶（BCR-ABL）癌基因转化会导致慢性髓系白血病（CML）。E-二十六（ets）转录因子 GA 结合蛋白（GABP）是一种包含 GABPα 和 GABPβ 蛋白的四聚体转录因子复合物。骨髓中编码 DNA 结合成分的 Gabpa 基因缺失导致 HSCs 细胞周期停滞和造血祖细胞严重丧失。Gabpα 的缺失阻止了 CML 的发展，尽管小鼠继续产生 BCR-ABL 表达的 Gabpα 缺失细胞数月，这些细胞可连续移植，并为次级受者的所有谱系做出贡献。生物信息学筛选鉴定出丝氨酸-苏氨酸激酶蛋白激酶 D2（PRKD2）为 HSCs 中 GABP 的潜在效应物。Gabpα 缺失的 HSCs 和祖细胞中 PRKD2 的表达明显降低。PRKD2 表达的降低或药物抑制会降低细胞周期，PRKD2 可挽救 Gabpα 缺失的 BCR-ABL 表达细胞的生长。因此，GABP 通过其对 PRKD2 的控制，是 HSC 细胞周期进入和 CML 发展所必需的。这为白血病提供了一个潜在的治疗靶点。
