Hydroxyurea (HU) is frequently used in the early phase of chronic myeloid leukemia (CML) to achieve cytoreduction prior to tyrosine kinase inhibitor therapy. However, its impact on CML stem and progenitor cells (SPC) remains largely unknown. This study utilized targeted proteo-transcriptomic expression data on 596 genes and 51 surface proteins in 60,000 CD14-CD34+ cells from chronic phase CML patients to determine effects of short-term HU treatment (4-19 days) on CML SPC. Peripheral blood and bone marrow samples were obtained from 17 CML patients eligible for short-term HU treatment (3 patients before and after HU, 7 patients before HU and 7 patients after HU) and subjected to single-cell CITE-sequencing and/or flow cytometry analysis. The analysis revealed enhanced frequencies of hemoglobin-expressing (HBA1, HBA2, HBB) erythroid progenitor cells in blood and bone marrow following HU treatment. In addition, there was an accumulation of cell subsets with S/G2/M phase-related gene and protein expression, likely representing cells arrested in, or progressing slowly through, the cell cycle. The increased frequency of cells in S/G2/M phase after HU was observed already among the most immature leukemic stem cells (LSC), and patients with a large fraction of LSC in the S/G2/M phase showed poor responsiveness to tyrosine kinase inhibitor treatment. We conclude that short-term HU treatment entails differentiation of erythroid progenitor cells and alters the characteristics of LSC in CML. The results imply that studies of LSC and progenitor populations in CML should take effects of initial HU therapy into account.

中文翻译：

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单细胞蛋白质转录组学分析揭示了早期慢性粒细胞白血病接受细胞减灭性羟基脲的患者干细胞和祖细胞特征的改变。


羟基脲 （胡） 经常用于慢性粒细胞白血病 （CML） 的早期阶段，以在酪氨酸激酶抑制剂治疗之前实现细胞减灭。然而，它对 CML 干细胞和祖细胞 （SPC） 的影响在很大程度上仍然未知。本研究利用慢性期 CML 患者 60,000 个 CD14-CD34 + 细胞中 596 个基因和 51 个表面蛋白的靶向蛋白质转录组表达数据来确定短期 胡 治疗 （4-19 天） 对 CML SPC 的影响。从 17 例符合短期 胡 治疗条件的 CML 患者 （胡 前后 3 例患者，胡 前7例患者和胡后7例患者） 获得外周血和骨髓样本，并进行单细胞 CITE 测序和/或流式细胞术分析。分析显示，胡 治疗后血液和骨髓中表达血红蛋白 （HBA1， HBA2， HBB） 的红系祖细胞的频率增加。此外，存在具有 S/G2/M 期相关基因和蛋白质表达的细胞亚群的积累，可能代表细胞停滞在细胞周期中或在细胞周期中缓慢进展。在最未成熟的白血病干细胞 （LSC） 中已经观察到 胡 后 S/G2/M 期细胞频率的增加，并且在 S/G2/M 期具有大量 LSC 的患者对酪氨酸激酶抑制剂治疗表现出较差的反应性。我们得出结论，短期 胡 治疗需要红系祖细胞分化并改变 CML 中 LSC 的特性。结果表明，对 CML 中 LSC 和祖细胞群的研究应考虑初始 胡 治疗的影响。