Myelodysplastic neoplasms (MDS) are myeloid neoplasms characterized by disordered differentiation of hematopoietic stem cells and a predisposition to acute myeloid leukemia (AML). The underline pathogenesis remains unclear. In this study, the trajectory of differentiation and mechanisms of leukemic transformation were explored through bioinformatics analysis of single-cell RNA-Seq data from hematopoietic stem and progenitor cells (HSPCs) in MDS patients. Among the HSPC clusters, the proportion of common myeloid progenitor (CMP) was the main cell cluster in the patients with excess blasts (EB)/ secondary AML. Cell cycle analysis indicated the CMP of MDS patients were in an active proliferative state. The genes involved in the cell proliferation, such as MAML3 and PLCB1, were up-regulated in MDS CMP. Further validation analysis indicated that the expression levels of MAML3 and PLCB1 in patients with MDS-EB were significantly higher than those without EB. Patients with high expression of PLCB1 had a higher risk of transformation to AML. PLCB1 inhibitor can suppress proliferation, induce cell cycle arrest, and activate apoptosis of leukemic cells in vitro. This study revealed the transcriptomic change of HSPCs in MDS patients along the pseudotime and indicated that PLCB1 plays a key role in the transformation of MDS into leukemia.

中文翻译：

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单细胞转录组学剖析骨髓增生异常肿瘤中造血干细胞的转录组变化

骨髓增生异常肿瘤（MDS）是一种髓系肿瘤，其特征是造血干细胞分化障碍和易患急性髓系白血病（AML）。潜在的发病机制仍不清楚。本研究通过对MDS患者造血干细胞和祖细胞（HSPC）的单细胞RNA-Seq数据进行生物信息学分析，探讨分化轨迹和白血病转化机制。在HSPC簇中，常见髓系祖细胞（CMP）的比例是过量母细胞（EB）/继发性AML患者的主要细胞簇。细胞周期分析表明MDS患者的CMP处于活跃的增殖状态。参与细胞增殖的基因，如 MAML3 和 PLCB1，在 MDS CMP 中上调。进一步验证分析表明，MDS-EB患者中MAML3和PLCB1的表达水平显着高于非EB患者。 PLCB1高表达的患者转化为AML的风险较高。 PLCB1抑制剂可以在体外抑制白血病细胞的增殖、诱导细胞周期停滞并激活白血病细胞的凋亡。本研究揭示了MDS患者假时间内HSPCs的转录组变化，表明PLCB1在MDS向白血病转化过程中发挥着关键作用。