Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.
Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.
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DOI：
10.1038/s41591-023-02636-6
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发表时间：
2023-12
期刊：
影响因子：
82.9
通讯作者：
Kent, David G.
中科院分区：
文献类型：
--
作者：
Chapman, Michael Spencer;Cull, Alyssa H.;Ciuculescu, Marioara F.;Esrick, Erica B.;Mitchell, Emily;Jung, Hyunchul;O'Neill, Laura;Roberts, Kirsty;Fabre, Margarete A.;Williams, Nicholas;Nangalia, Jyoti;Quinton, Joanne;Fox, James M.;Pellin, Danilo;Makani, Julie;Armant, Myriam;Williams, David A.;Campbell, Peter J.;Kent, David G.
基因治疗(GT)为镰状细胞病(SCD)患者提供了一种潜在的治疗选择；然而，GT临床试验中髓系恶性肿瘤的发生引起了人们的关注，并有几种假定的机制。在这里，我们使用全基因组测序来追踪6名SCD患者在GT前后的造血干细胞(HSCs)，以绘制基因修饰和未修饰HSCs的体细胞突变和克隆图谱。在GT前，系统发育树是高度多克隆的，在一些(但不是全部)患者中，每细胞的突变负荷增加。GT后，在基因修饰或未修饰的细胞中没有发现克隆性扩张；然而，在转基因和未修饰的细胞中都观察到了与髓系肿瘤或克隆性造血相关的潜在驱动突变的频率增加(特别是DNMT3A和EZH2突变克隆)，这表明在GT期间对突变克隆的选择是积极的。这项工作揭示了SCD中HSC克隆动力学和GT后的突变情况，突出了一些含有预先存在的驱动程序突变的HSC的增强适合性。未来的研究应该定义突变克隆的长期命运，包括对与髓系肿瘤相关的扩张的任何贡献。对接受过自体基因治疗的6名镰状细胞病患者的造血干细胞进行分析，发现含有克隆性造血和血液恶性肿瘤相关基因突变的细胞具有正选择压力。
Gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, with several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six patients with SCD at pre- and post-GT time points to map the somatic mutation and clonal landscape of gene-modified and unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified among gene-modified or unmodified cells; however, an increased frequency of potential driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) was observed in both genetically modified and unmodified cells, suggesting positive selection of mutant clones during GT. This work sheds light on HSC clonal dynamics and the mutational landscape after GT in SCD, highlighting the enhanced fitness of some HSCs harboring pre-existing driver mutations. Future studies should define the long-term fate of mutant clones, including any contribution to expansions associated with myeloid neoplasms. Analysis of hematopoietic stem cells from six individuals with sickle cell disease who had been treated with autologous gene therapy revealed positive selective pressure on cells containing mutations in genes associated with clonal hematopoiesis and hematological malignancies.
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DOI：
10.1056/nejmoa1700554
发表时间：
2017-10-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eichler F;Duncan C;Musolino PL;Orchard PJ;De Oliveira S;Thrasher AJ;Armant M;Dansereau C;Lund TC;Miller WP;Raymond GV;Sankar R;Shah AJ;Sevin C;Gaspar HB;Gissen P;Amartino H;Bratkovic D;Smith NJC;Paker AM;Shamir E;O'Meara T;Davidson D;Aubourg P;Williams DA
通讯作者：
Williams DA
影响因子：
158.5
作者：
Hacein-Bey-Abina, S;Le Deist, F;Leiva, L
通讯作者：
Leiva, L
影响因子：
23.9
作者：
de Kanter JK;Peci F;Bertrums E;Rosendahl Huber A;van Leeuwen A;van Roosmalen MJ;Manders F;Verheul M;Oka R;Brandsma AM;Bierings M;Belderbos M;van Boxtel R
通讯作者：
van Boxtel R
影响因子：
6.5
作者：
Alzahrani M;Damlaj M;Jeffries N;Alahmari B;Singh A;Rondelli D;Tisdale JF;Saraf SL;Hsieh MM
通讯作者：
Hsieh MM
影响因子：
64.8
作者：
Coorens, Tim H. H.;Moore, Luiza;Stratton, Michael R.
通讯作者：
Stratton, Michael R.