Trojani Alessandra, Pungolino Ester, Di Camillo Barbara, Bossi Luca Emanuele, Palumbo Cassandra, D'adda Mariella, Perego Alessandra, Turrini Mauro, Elena Chiara, Borin Lorenza Maria, Iurlo Alessandra, Malato Simona, Spina Francesco, Latargia Maria Luisa, Spedini Pierangelo, Artale Salvatore, Anghilieri Michela, Carraro Maria Cristina, Bucelli Cristina, Beghini Alessandro, Cairoli Roberto
Department of Hematology and Oncology, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy.
Department of Information Engineering, University of Padova, 35131 Padova, Italy.
Cancers (Basel). 2025 Mar 18;17(6):1022. doi: 10.3390/cancers17061022.
Chronic-Phase Chronic Myeloid Leukemia (C-PCML) is defined by the presence of the fusion 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.
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).
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.
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.
慢性期慢性髓性白血病（C-PCML）由融合基因的存在所定义，该融合基因编码一种酪氨酸激酶蛋白，可驱动白血病干细胞（LSC）的不受控制的增殖和存活。尼洛替尼是一种酪氨酸激酶抑制剂，通过减少异常信号通路来靶向BCR-ABL1的活性，而这些异常信号通路会驱动LSC的再生。尽管尼洛替尼有此作用，但仍有一群有韧性的LSC存在于骨髓（BM）中，并且确实可导致慢性髓性白血病患者的复发和病情进展。
我们研究对79例慢性期慢性髓性白血病患者诊断时骨髓CD34+/lin-细胞的基因表达谱（GEP）进行了研究，并与这些患者接受尼洛替尼治疗12个月后的骨髓CD34+/lin-细胞以及10名供体的正常对照细胞（CTRLs）进行比较。
GEP分析在这些比较中鉴定出3012个显著差异表达的基因。其中，我们重点关注与八个关键KEGG通路相关的某些关键基因：慢性髓性白血病、细胞周期、JAK-STAT、PI3K-Akt、MAPK、Ras、NF-kB和ABC转运蛋白。在这些通路中，我们观察到与尼洛替尼治疗12个月及CTRLs相比，诊断时几个基因上调。
我们观察到，与CTRLs相比，尼洛替尼治疗12个月后，诊断时存在的某些转录组特征仍然存在。这表明尼洛替尼可能施加了选择性压力，可能支持LSC的存活和自我更新。对这些通路的未来深入了解可能有助于确定治疗靶点，以改善慢性髓性白血病的治疗结果。
