cMYB is involved in the regulation of fetal hemoglobin production in adults
cMYB is involved in the regulation of fetal hemoglobin production in adults
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DOI：
10.1182/blood-2006-01-008912
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发表时间：
2006-08-01
期刊：
影响因子：
20.3
通讯作者：
Thein, Swee Lay
中科院分区：
文献类型：
--
作者：
Jiang, Jie;Best, Steve;Thein, Swee Lay
一个控制HbF水平的数量性状基因座（QTL）先前已被定位到染色体6 q23的亚洲-印度的β地中海贫血和胎儿血红蛋白（HPFH）的遗传性持久性。五个蛋白质编码基因，ALDH 8A 1，HBS 1 L，cMYB，AHI 1和PDE 7 B位于6 q23的1.5兆碱基（Mb）候选区间。为了直接测序，我们通过实时定量逆转录-聚合酶链反应（RT-PCR）比较了12名HbF水平升高的个体和14名HbF水平正常的个体在成人红细胞生成过程中这5个基因的表达谱。两个基因，cMYB和HBS 1 L，表现出同时转录下调与HbF水平升高的个人。转染K562细胞编码人cMYB和HBS 1 L基因的cDNA显示，虽然异位cMYB的过表达抑制γ-珠蛋白基因的表达，但HBS 1 L的过表达没有影响。低水平的cMYB与低细胞扩增、加速的红系成熟和红系细胞培养物中较高数量的巨噬细胞相关。这些观察结果表明，cMYB的内在水平的差异可能是成人HbF水平变化的原因。cMYB影响γ-β-珠蛋白转换的可能机制进行了讨论。
A quantitative trait locus (QTL) controlling HbF levels has previously been mapped to chromosome 6q23 in an Asian-Indian kindred with beta thalassemia and helerocellular hereditary persistence of fetal hemoglobin (HPFH). Five protein-coding genes, ALDH8A1, HBS1L, cMYB, AHI1, and PDE7B reside in this 1.5-megabase (Mb) candidate interval of 6q23. To direct sequencing efforts we compared the expression profiles of these 5 genes between 12 individuals with elevated and 14 individuals with normal HbF levels during adult erythropoiesis by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Two genes, cMYB and HBS1L, demonstrated simultaneous transcriptional down-regulation in individuals with elevated HbF levels. Transfection of K562 cells encoding human cDNA of cMYB and HBS1L genes showed that, although overexpression of ectopic cMYB inhibited gamma-globin gene expression, overexpression of HBS1L had no effect. Low levels of cMYB were associated with low cell expansions, accelerated erythroid maturation, and higher number of macrophages in erythroid cell culture. These observations suggest that differences in the intrinsic levels of cMYB may account for some of the variation in adult HbF levels. The possible mechanism of cMYB influencing gamma- to beta-globin switching is discussed.