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Abstract：
While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.
摘要：
虽然患有del(5q)(del(5q)MDS)的骨髓增生异常综合征包括明确定义的血液学亚组,其起源的分子基础仍然未知。使用来自del（5q）MDS患者的CD34+祖细胞上的单细胞RNA-seq（scRNA-seq），我们已经确定了包含缺失的细胞，表征这种遗传损伤对疾病发病机理和治疗反应的转录影响。有趣的是,del(5q)和non-del(5q)细胞都呈现相似的转录损伤，表明所有细胞，不仅仅是那些隐藏删除的人，可能导致异常的造血分化。然而,基因调控网络（GRN）分析揭示了一组显示异常活性的调控子，这些调控子只能在del（5q）细胞中触发改变的造血，指出这些细胞在疾病表型中的作用更加突出。在del(5q)MDS患者中，来那度胺治疗后达到血液学反应，该药物在del（5q）和non-del（5q）细胞中恢复了几种转录变化，但是其他病变仍然存在，这可能是未来潜在复发的原因。此外，血液学反应的缺乏与来那度胺不能逆转转录改变有关。总的来说，这项研究揭示了可能导致del（5q）MDS发病机制和治疗反应的转录改变。
