Comparative Analysis of the Genetic Variants in Haematopoietic Stem/Progenitor and Mesenchymal Stem Cell Compartments in de novo Myelodysplastic Syndromes
Comparative Analysis of the Genetic Variants in Haematopoietic Stem/Progenitor and Mesenchymal Stem Cell Compartments in de novo Myelodysplastic Syndromes
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DOI：
10.1016/j.bcmd.2021.102535
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发表时间：
2021-01-15
影响因子：
2.3
通讯作者：
Dissanayake, Vajira H. W.
中科院分区：
文献类型：
--
作者：
Bandara, W. M. Manoj S.;Rathnayake, A. J. Iresha S.;Dissanayake, Vajira H. W.
骨髓增生异常综合征（MDS）是一种血液学克隆性疾病。骨髓间充质干细胞（MSC）与造血干细胞和祖细胞（HSPC）相互作用以调节造血。我们研究了20例南亚新生MDS患者中同一患者骨髓来源的CD34（+）HSPC和MSC的遗传变异谱。HSPC和MSC中分别有42个基因（变体471）和38个基因（变体232）发生突变，大多数（97%）是不同的变体。变异包括已知和新的，预测为致病性的变异。在这两种细胞类型中，最常突变的基因是TET 2、KDM 6A、BCOR、EZH 2和ASXL。DNA甲基化和染色质重塑在两种细胞类型中均以高频率受到影响。RNA剪接在HSPCs中受到更多的影响。内聚复合体和表观遗传机制中的基因变体被证明是共存的。我们报告了来自南亚队列的MSC和CD34（+）HSPC的变异特征，其中新的变异有可能作为MDS的生物标志物进行进一步研究。局限于每个细胞区室的不同变体表明遗传变异发生在谱系定型之后。
Myelodysplastic Syndromes (MDS) are hematological clonal disorders. Bone marrow (BM) mesenchymal stem cells (MSCs) interact with the haematopoietic stem and progenitor cells (HSPCs) to regulate haematopoiesis. We studied the genetic variation profiles of BM derived CD34(+) HSPCs and MSCs of same patient in a South Asian de novo MDS cohort with 20 patients. A total of 42 genes (variants 471) and 38 genes (variants 232) were mutated in HSPCs and MSCs respectively and majority (97%) were distinct variants. Variants included both known and novel, with variants predicted as pathogenic. In both cell types, most frequently mutated genes were TET2, KDM6A, BCOR, EZH2 and ASXL. DNA methylation and chromatin remodeling were shown to be affected in both cell types with a high frequency. RNA splicing was affected more in HSPCs. Gene variants in the cohesion complex and epigenetic mechanisms were shown to co-exist. We report variant profile of MSCs and CD34(+) HSPCs from a South Asian cohort, with novel variants with potential for further study as biomarkers in MDS. Distinct variants confined to each cellular compartment indicate that the genetic variations occur following lineage commitment.