O'Brien Kelly A, Farrar Jason E, Vlachos Adrianna, Anderson Stacie M, Tsujiura Crystiana A, Lichtenberg Jens, Blanc Lionel, Atsidaftos Eva, Elkahloun Abdel, An Xiuli, Ellis Steven R, Lipton Jeffrey M, Bodine David M
Genetics and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD.
Arkansas Children's Research Institute, Little Rock, AR.
Blood. 2017 Jun 8;129(23):3111-3120. doi: 10.1182/blood-2017-01-760462. Epub 2017 Apr 4.
Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by erythroid hypoplasia, usually without perturbation of other hematopoietic lineages. Approximately 65% of DBA patients with autosomal dominant inheritance have heterozygous mutations or deletions in ribosomal protein (RP) genes while <1% of patients with X-linked inheritance have been identified with mutations in the transcription factor Erythroid cells from patients with DBA have not been well characterized, and the mechanisms underlying the erythroid specific effects of either RP or associated DBA remain unclear. We have developed an ex vivo culture system to expand peripheral blood CD34 progenitor cells from patients with DBA and differentiate them into erythroid cells. Cells from patients with RP or mutations showed decreased proliferation and delayed erythroid differentiation in comparison with controls. RNA transcript analyses of erythroid cells from controls and patients with RP or mutations showed distinctive differences, with upregulation of heme biosynthesis genes prominently in RP-mediated DBA and failure to upregulate components of the translational apparatus in -mediated DBA. Our data show that dysregulation of translation is a common feature of DBA caused by both RP and mutations. This trial was registered at www.clinicaltrials.gov as #NCT00106015.
先天性纯红细胞再生障碍性贫血（DBA）是一种先天性骨髓衰竭综合征，其特征为红系造血发育不全，通常不累及其他造血谱系。约65%常染色体显性遗传的DBA患者在核糖体蛋白（RP）基因中存在杂合突变或缺失，而X连锁遗传患者中仅有不到1%被发现存在转录因子突变。DBA患者的红系细胞尚未得到充分研究，RP或相关DBA导致红系特异性效应的机制仍不清楚。我们开发了一种体外培养系统，用于扩增DBA患者的外周血CD34祖细胞并将其分化为红系细胞。与对照组相比，RP或突变患者的细胞增殖减少且红系分化延迟。对对照组以及RP或突变患者红系细胞的RNA转录分析显示出显著差异，在RP介导的DBA中血红素生物合成基因显著上调，而在介导的DBA中翻译装置的组成成分未能上调。我们的数据表明，翻译失调是由RP和突变导致的DBA的共同特征。该试验已在www.clinicaltrials.gov上注册，注册号为#NCT00106015。
