耐免疫治疗的急性淋巴细胞白血病细胞表现出降低的CD19和CD22表达和BTK通路依赖性
Sarah Aminov1, Orsi Giricz1, David T Melnekoff2
1Department of Oncology, Blood Cancer Institute, Montefiore Einstein Comprehensive Cancer Center, Bronx, New York, USA.
The Journal of clinical investigation
|February 20, 2024
概括
对CD19免疫疗法的耐药性可能导致白血病细胞中CD19和CD22的表达减少. 这些耐药细胞可能会依赖布鲁顿.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 基因组学就是基因组学.
背景情况:
- 针对CD19的疗法 (例如,CAR-T细胞) 改善了B细胞恶性瘤的结果.
- 由于癌细胞的CD19表达率较低,治疗耐药性可能导致疾病复发.
- 了解适应性耐药机制对于克服治疗失败至关重要.
研究的目的:
- 开发和描述一种适应性抗性对CD19向治疗的体外模型.
- 研究白血病细胞发展抗性的分子和功能变化.
- 为了确定CD19抗性B细胞恶性瘤中潜在的替代治疗点.
主要方法:
- 使用白血病细胞长期暴露于CD19免疫毒素的实验室模型的开发.
- 单细胞RNA测序 (scRNA-Seq) 用于分析转录变化.
- 质量细胞计用于蛋白质表达分析和ATAC-Seq用于染色体可访问性分析.
主要成果:
- 抗性白血病细胞表现出CD19和CD22抗原的表达减少.
- 在耐药细胞中观察到CD19和CD22基因促进体的染色质可访问性降低.
- 耐药细胞的生长速度较慢,维护了B细胞受体信号传递,对BTK和MEK抑制剂的敏感性.
结论:
- 对CD19免疫疗法的适应性耐药性可以诱导CD19和CD22的共降调节.
- 在复发性B-ALLCD19后CAR-T治疗中观察到CD19和CD22表达的丧失.
- 抗CD19的细胞可能依赖于布鲁顿氨酸激酶 (BTK) 途径,这表明潜在的治疗漏洞.
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