文章：

尼洛替尼治疗12个月后，慢性期慢性髓系白血病（CP-CML）患者骨髓CD34+/lin−细胞的基因表达谱与初诊时及健康对照者相应细胞存在显著差异。

Bone Marrow CD34+/lin− Cells of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) After 12 Months of Nilotinib Treatment Exhibit a Different Gene Expression Signature Compared to the Diagnosis and the Corresponding Cells from Healthy Subjects

原文发布日期：18 March 2025

DOI: 10.3390/cancers17061022

类型: Article

开放获取: 是

英文摘要：

Background: Chronic-Phase Chronic Myeloid Leukemia (C-PCML) is defined by the presence of theBCR-ABL1fusion gene, which encodes a tyrosine kinase protein that drives the uncontrolled proliferation and survival of leukemic stem cells (LSCs). Nilotinib, a tyrosine kinase inhibitor, targets the activity of BCR-ABL1 by reducing aberrant signaling pathways, which drive the regeneration of LSCs. Despite nilotinib’s action, a population of resilient LSCs persist in the bone marrow (BM) and can indeed drive relapse and progression in CML patients. Methods: Our study investigated the gene expression profiling (GEP) of BM CD34+/lin− cells from 79 CP-CML patients at diagnosis, compared to the BM CD34+/lin− cells from the same patients after 12 months of nilotinib treatment and to the normal counterpart cells from 10 donors (CTRLs). Results: GEP analyses identified 3012 significantly differentially expressed genes across these comparisons. Among these, we focused on certain key genes associated with eight crucial KEGG pathways: CML, cell cycle, JAK-STAT, PI3K-Akt, MAPK, Ras, NF-kB, and ABC transporters. Within these pathways, we observed the up-regulation of several genes at diagnosis compared to both 12 months of nilotinib treatment and the CTRLs. Conclusions: We observed that certain transcriptome features present at diagnosis persisted after 12 months of nilotinib treatment, compared to CTRLs. This suggests that nilotinib may exert selective pressure, potentially supporting the survival and self-renewal of LSCs. Future insights into these pathways could help identify therapeutic targets to improve outcomes in CML.

摘要翻译： 

背景：慢性期慢性髓系白血病（C-PCML）的特征是存在BCR-ABL1融合基因，该基因编码一种酪氨酸激酶蛋白，驱动白血病干细胞（LSCs）的异常增殖与存活。尼洛替尼作为一种酪氨酸激酶抑制剂，通过抑制异常信号通路来靶向BCR-ABL1的活性，从而阻断LSCs的再生。尽管尼洛替尼具有治疗作用，但骨髓（BM）中仍存在一群具有耐药性的LSCs，这些细胞可导致CML患者的复发与疾病进展。方法：本研究通过基因表达谱（GEP）分析，比较了79例初诊CP-CML患者骨髓CD34+/lin−细胞、同一患者接受尼洛替尼治疗12个月后的骨髓CD34+/lin−细胞，以及10例健康供者（CTRLs）的正常对应细胞。结果：GEP分析共鉴定出3012个显著差异表达基因。我们重点关注了与八个关键KEGG通路相关的特定基因：CML通路、细胞周期通路、JAK-STAT通路、PI3K-Akt通路、MAPK通路、Ras通路、NF-κB通路及ABC转运蛋白通路。在这些通路中，我们观察到初诊时多个基因的表达水平相较于尼洛替尼治疗12个月后及CTRLs均呈现上调。结论：研究发现，与CTRLs相比，初诊时存在的某些转录组特征在尼洛替尼治疗12个月后仍然持续存在。这表明尼洛替尼可能施加了选择性压力，潜在地支持了LSCs的存活与自我更新。未来对这些通路的深入研究将有助于识别治疗靶点，以改善CML患者的临床结局。

原文链接：

Bone Marrow CD34+/lin− Cells of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) After 12 Months of Nilotinib Treatment Exhibit a Different Gene Expression Signature Compared to the Diagnosis and the Corresponding Cells from Healthy Subjects