泊纳替尼与STAT5抑制剂匹莫齐联合协同治疗应用可通过调节慢性髓性白血病细胞的细胞因子表达网络克服耐药性

IF 1.9 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Interferon and Cytokine Research Pub Date : 2024-04-01 DOI:10.1089/jir.2023.0170
Burcin Tezcanli Kaymaz, Nurcan Gumus, Besne Celik, İlayda Alcitepe, Cigir Biray Avci, Cagdas Aktan
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引用次数: 0

摘要

慢性髓性白血病(CML)是一种克隆性骨髓增生性血液病,其特征是嵌合断点簇区/阿贝尔森激酶1(BCR::ABL1)肿瘤蛋白;它在CML分子病理学、诊断、治疗以及酪氨酸激酶抑制剂(TKI)为基础的治疗的成功率和耐受性可能产生的耐药性中起着关键作用。受细胞因子信号网络影响的转录因子 STAT5 构成性信号转导触发了以 BCR::ABL1 为基础的 CML 发病机制,也与获得性 TKI 耐药性有关。针对BCR::ABL1的不成功治疗方法,尤其是使用泊纳替尼的三线治疗,仍需进一步开发其他联合策略来克服耐药性。由于 STAT5 抑制剂匹莫齐特与泊纳替尼联合治疗对 TKI 耐药的 CML 细胞具有高效、协同的治疗效果,本研究通过确定亲代 CML 细胞和泊纳替尼耐药 CML 细胞中不同细胞因子的体外表达谱,重点研究了泊纳替尼反应机制放大的根本原因。结果显示,与敏感细胞相比,白细胞介素(IL)1B、IL9和IL12A-B的表达增加了2倍,而IL18的表达下调了2倍。重要的是,泊纳替尼治疗会上调泊纳替尼耐药细胞中23个干扰素和IL基因中21个基因的表达,而用匹莫齐特或联合剂量治疗会导致19个不同细胞因子基因的表达减少,例如炎性细胞因子、IL1A-B和IL6或与支持肿瘤进展、白血病干细胞生长或生存率低有关的细胞因子基因,如IL3、IL8、IL9、IL10、IL12或IL15。基因本体(GO)和京都基因与基因组百科全书(KEGG)通路分析结果显示,这些基因主要富集在通过Janus激酶/信号转导和激活转录通路调控受体信号转导、细胞因子-细胞因子受体相互作用和造血细胞系等方面。蛋白质-蛋白质相互作用分析表明,IL2、IL6、IL15、IFNG等出现在通路的前几位,表明它们在网络中具有高度的中心性和重要性。因此,匹莫齐特可能是一种很有前途的药物,可用于支持治疗泊纳替尼耐药的TKI疗法。这项研究将有助于阐明细胞因子在泊纳替尼耐药中的作用,并推动新疗法的开发,将STAT5抑制剂匹莫齐特与TKIs联合使用。
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Ponatinib and STAT5 Inhibitor Pimozide Combined Synergistic Treatment Applications Potentially Overcome Drug Resistance via Regulating the Cytokine Expressional Network in Chronic Myeloid Leukemia Cells.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematological disease characterized by the chimeric breakpoint-cluster region/Abelson kinase1 (BCR::ABL1) oncoprotein; playing a pivotal role in CML molecular pathology, diagnosis, treatment, and possible resistance arising from the success and tolerance of tyrosine kinase inhibitor (TKI)-based therapy. The transcription factor STAT5 constitutive signaling, which is influenced by the cytokine signaling network, triggers BCR::ABL1-based CML pathogenesis and is also relevant to acquired TKI resistance. The unsuccessful therapeutic approaches targeting BCR::ABL1, in particular third-line therapy with ponatinib, still need to be further developed with alternative combination strategies to overcome drug resistance. As treatment with the STAT5 inhibitor pimozide in combination with ponatinib resulted in an efficient and synergistic therapeutic approach in TKI-resistant CML cells, this study focused on identifying the underlying amplification of ponatinib response mechanisms by determining different cytokine expression profiles in parental and ponatinib-resistant CML cells, in vitro. The results showed that expression of interleukin (IL) 1B, IL9, and IL12A-B was increased by 2-fold, while IL18 was downregulated by 2-fold in the ponatinib-resistant cells compared to sensitive ones. Importantly, ponatinib treatment upregulated the expression of 21 of the 23 interferon and IL genes in the ponatinib-resistant cells, while treatment with pimozide or a combination dose resulted in a reduction in the expression of 19 different cytokine genes, such as for example, inflammatory cytokines, IL1A-B and IL6 or cytokine genes associated with supporting tumor progression, leukemia stem cell growth or poor survival, such as IL3, IL8, IL9, IL10, IL12, or IL15. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis results showed that the genes were mainly enriched in the regulation of receptor signaling through the Janus kinase/signal transducer and activator of transcription pathway, cytokine-cytokine receptor interaction, and hematopoietic cell lineage. Protein-protein interaction analysis showed that IL2, IL6, IL15, IFNG, and others appeared in the top lists of pathways, indicating their high centrality and importance in the network. Therefore, pimozide could be a promising agent to support TKI therapies in ponatinib resistance. This research would help to clarify the role of cytokines in ponatinib resistance and advance the development of new therapeutics to utilize the STAT5 inhibitor pimozide in combination with TKIs.

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来源期刊
CiteScore
3.80
自引率
0.00%
发文量
78
审稿时长
2.2 months
期刊介绍: Journal of Interferon & Cytokine Research (JICR) provides the latest groundbreaking research on all aspects of IFNs and cytokines. The Journal delivers current findings on emerging topics in this niche community, including the role of IFNs in the therapy of diseases such as multiple sclerosis, the understanding of the third class of IFNs, and the identification and function of IFN-inducible genes.
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