Abdullah J M, Li X, Nachtman R G, Jurecic R
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136, USA.
Blood Cells Mol Dis. 2001 Jan-Feb;27(1):320-33. doi: 10.1006/bcmd.2001.0390.
Through differential screening of mouse hematopoietic stem cell (HSC) and progenitor subtracted cDNA libraries we have identified a HSC-specific transcript that represents a novel RING finger gene, named FLRF (fetal liver ring finger). FLRF represent a novel evolutionarily highly conserved RING finger gene, present in Drosophila, zebrafish, Xenopus, mouse, and humans. Full-length cDNA clones for mouse and human gene encode an identical protein of 317 amino acids with a C3HC4 RING finger domain at the amino terminus. During embryonic hematopoiesis FLRF is abundantly transcribed in mouse fetal liver HSC (Sca-1+c-kit+AA4.1+Lin- cells), but is not expressed in progenitors (AA4.1-). In adult mice FLRF is not transcribed in a highly enriched population of bone marrow HSC (Rh-123lowSca-1+c-kit+Lin- cells). Its expression is upregulated in a more heterogeneous population of bone marrow HSC (Lin-Sca-1+ cells), downregulated as they differentiate into progenitors (Lin-Sca-1- cells), and upregulated as progenitors differentiate into mature lymphoid and myeloid cell types. The human FLRF gene that spans a region of at least 12 kb and consists of eight exons was localized to chromosome 12q13, a region with frequent chromosome aberrations associated with multiple cases of acute myeloid leukemia and non-Hodgkin's lymphoma. The analysis of the genomic sequence upstream of the first exon in the mouse and human FLRF gene has revealed that both putative promoters contain multiple putative binding sites for several hematopoietic (GATA-1, GATA-2, GATA-3, Ikaros, SCL/Tal-1, AML1, MZF-1, and Lmo2) and other transcription factors, suggesting that mouse and human FLRF expression could be regulated in a developmental and cell-specific manner during hematopoiesis. Evolutionary conservation and differential expression in fetal and adult HSC and progenitors suggest that the FLRF gene could play an important role in HSC/progenitor cell lineage commitment and differentiation and could be involved in the etiology of hematological malignancies.
通过对小鼠造血干细胞（HSC）和祖细胞消减cDNA文库的差异筛选，我们鉴定出一种HSC特异性转录本，它代表了一个新的环状结构域基因，命名为FLRF（胎儿肝脏环状结构域基因）。FLRF是一个新的进化上高度保守的环状结构域基因，存在于果蝇、斑马鱼、非洲爪蟾、小鼠和人类中。小鼠和人类基因的全长cDNA克隆编码一个由317个氨基酸组成的相同蛋白质，在氨基末端有一个C3HC4环状结构域。在胚胎造血过程中，FLRF在小鼠胎儿肝脏HSC（Sca-1+c-kit+AA4.1+Lin-细胞）中大量转录，但在祖细胞（AA4.1-）中不表达。在成年小鼠中，FLRF在高度富集的骨髓HSC群体（Rh-123lowSca-1+c-kit+Lin-细胞）中不转录。其表达在骨髓HSC的更异质群体（Lin-Sca-1+细胞）中上调，在它们分化为祖细胞（Lin-Sca-1-细胞）时下调，而在祖细胞分化为成熟淋巴细胞和髓细胞类型时上调。跨越至少12kb区域且由八个外显子组成的人类FLRF基因定位于染色体12q13，该区域常出现与多例急性髓性白血病和非霍奇金淋巴瘤相关的染色体畸变。对小鼠和人类FLRF基因第一个外显子上游基因组序列的分析表明，两个推定的启动子都含有多个针对几种造血（GATA-1、GATA-2、GATA-3、Ikaros、SCL/Tal-1、AML1、MZF-1和Lmo2）及其他转录因子的推定结合位点，这表明小鼠和人类FLRF的表达在造血过程中可能以发育和细胞特异性的方式受到调控。在胎儿和成年HSC及祖细胞中的进化保守性和差异表达表明，FLRF基因可能在HSC/祖细胞谱系定向和分化中起重要作用，并且可能与血液系统恶性肿瘤的病因学有关。
