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靶向白细胞介素-17A 可增强费城染色体阳性 B 细胞急性淋巴细胞白血病伊马替尼的疗效。

Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia.

机构信息

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.

出版信息

Nat Commun. 2024 Jan 3;15(1):203. doi: 10.1038/s41467-023-44270-3.

DOI:10.1038/s41467-023-44270-3
PMID:38172124
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10764960/
Abstract

Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph B-ALL patients. IL-17A promotes the progression of Ph B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph B-ALL progression and suggest potential therapeutic options for Ph B-ALL with Th17-enriched niches.

摘要

白血病细胞失调的造血龛重塑导致支持白血病发生和耐药性的免疫介质失衡。针对免疫龛可能改善费城染色体阳性 B-ALL（Ph B-ALL）的疾病进展和酪氨酸激酶抑制剂（TKI）耐药性。在这里，我们表明 Th17 细胞和 IL-17A 表达在 Ph B-ALL 患者中明显升高。IL-17A 促进 Ph B-ALL 的进展。在机制上，IL-17A 在 Ph B-ALL 细胞中激活 BCR-ABL、IL6/JAK/STAT3 和 NF-kB 信号通路，导致细胞增殖和存活旺盛。此外，IL-17A 激活的 Ph B-ALL 细胞分泌趋化因子 CXCL16，反过来促进 Th17 分化，吸引 Th17 细胞并形成支持白血病进展的正反馈环。这些数据表明 Th17 细胞参与 Ph B-ALL 的进展，并为富含 Th17 细胞的龛位的 Ph B-ALL 提供潜在的治疗选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/a5f4826da761/41467_2023_44270_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/f77453780708/41467_2023_44270_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/b4a852ede993/41467_2023_44270_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/5b5a746691c6/41467_2023_44270_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/34e0c481b4e4/41467_2023_44270_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/7227e7764204/41467_2023_44270_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/5f717297816a/41467_2023_44270_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/a5f4826da761/41467_2023_44270_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/f77453780708/41467_2023_44270_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/07d287fc0ee7/41467_2023_44270_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/b4a852ede993/41467_2023_44270_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/5b5a746691c6/41467_2023_44270_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/34e0c481b4e4/41467_2023_44270_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/7227e7764204/41467_2023_44270_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/5f717297816a/41467_2023_44270_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ecd/10764960/a5f4826da761/41467_2023_44270_Fig8_HTML.jpg

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