Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia.
Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia.
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DOI：
10.1016/j.exphem.2021.10.005
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发表时间：
2022-01
影响因子：
2.6
通讯作者：
Flygare J
中科院分区：
文献类型：
--
作者：
Sjögren SE;Chen J;Mattebo A;Alattar AG;Karlsson H;Siva K;Soneji S;Tedgård U;Chen JJ;Gram M;Flygare J
Diamond-Blackfan贫血（DBA）是一种罕见的遗传性疾病，患者在正常细胞的骨髓中缺乏红细胞前体。大多数（但不是全部）患者携带RPS19等核糖体蛋白突变，这表明mRNA翻译受损和核糖体应激是导致红细胞前体耗损的致病机制。为了进一步了解DBA的疾病机制，我们对750个假设影响DBA病理生理的基因进行了定制的短发卡RNA （shRNA）筛选。其中有两个shrna靶向红系特异性血红素调控的eIF2a激酶（HRI）， HRI是mRNA翻译的负调控因子。本研究表明shrna介导的HRI沉默或缺失一个HRI等位基因可改善rps19缺陷红系前体的扩增，并改善rps19缺陷动物的贫血表型。我们发现rps19缺陷的红母细胞具有升高的未结合的细胞内血红素水平，这是由HRI杂合性正常化的。此外，通过用血红素清扫剂α -1微球蛋白（A1M）治疗细胞，靶向血红素水平升高，以疾病特异性方式增加rps19缺陷红细胞前体的增殖和降低血红素水平。HRI杂合性，而非A1M处理，也降低了rps19缺陷细胞中观察到的p53活性升高，表明p53激活是由核糖体应激和mRNA翻译异常引起的，而不是rps19缺陷中血红素超载引起的。总之，这些发现表明靶向血红素水平升高是一种有希望的DBA新治疗策略。
Diamond-Blackfan anemia (DBA) is a rare genetic disorder in which patients present a scarcity of erythroid precursors in an otherwise normocellular bone marrow. Most, but not all, patients carry mutations in ribosomal proteins such as RPS19, suggesting that compromised mRNA translation and ribosomal stress are pathogenic mechanisms causing depletion of erythroid precursors. To gain further insight to disease mechanisms in DBA, we performed a custom short hairpin RNA (shRNA) based screen against 750 genes hypothesized to affect DBA pathophysiology. Among the hits were two shRNAs against the erythroid specific heme-regulated eIF2a kinase (HRI), which is a negative regulator of mRNA translation. This study shows that shRNA-mediated HRI silencing or loss of one HRI allele improves expansion of Rps19-deficient erythroid precursors, as well as improves the anemic phenotype in Rps19-deficient animals. We found that Rps19-deficient erythroblasts have elevated levels of unbound intracellular heme, which is normalized by HRI heterozygosity. Additionally, targeting elevated heme levels by treating cells with the heme scavenger alpha-1-microglobulin (A1M), increased proliferation of Rps19-deficient erythroid precursors and decreased heme levels in a disease-specific manner. HRI heterozygosity, but not A1M treatment, also decreased the elevated p53 activity observed in Rps19-deficient cells, indicating that p53 activation is caused by ribosomal stress and aberrant mRNA translation and not heme overload in Rps19-deficiency. Together, these findings suggest that targeting elevated heme levels is a promising new treatment strategy for DBA.
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DOI：
10.1126/science.aao0932
发表时间：
2018-07-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Grevet JD;Lan X;Hamagami N;Edwards CR;Sankaranarayanan L;Ji X;Bhardwaj SK;Face CJ;Posocco DF;Abdulmalik O;Keller CA;Giardine B;Sidoli S;Garcia BA;Chou ST;Liebhaber SA;Hardison RC;Shi J;Blobel GA
通讯作者：
Blobel GA
影响因子：
20.3
作者：
Flygare, Johan;Aspesi, Anna;Ellis, Steven R.
通讯作者：
Ellis, Steven R.
影响因子：
64.5
作者：
Khajuria RK;Munschauer M;Ulirsch JC;Fiorini C;Ludwig LS;McFarland SK;Abdulhay NJ;Specht H;Keshishian H;Mani DR;Jovanovic M;Ellis SR;Fulco CP;Engreitz JM;Schütz S;Lian J;Gripp KW;Weinberg OK;Pinkus GS;Gehrke L;Regev A;Lander ES;Gazda HT;Lee WY;Panse VG;Carr SA;Sankaran VG
通讯作者：
Sankaran VG
影响因子：
4.6
作者：
Juli, Giada;Gismondi, Angelo;Loreni, Fabrizio
通讯作者：
Loreni, Fabrizio
影响因子：
1.6
作者：
Kwasek, Anna;Osmark, Peter;Wasylewski, Zygmunt
通讯作者：
Wasylewski, Zygmunt