JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL.

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-21 DOI:10.1084/jem.20230681
Shifa Khaja Saleem, Sarah Decker, Sandra Kissel, Marcus Bauer, Dmitry Chernyakov, Daniela Bräuer-Hartmann, Konrad Aumann, Claudia Wickenhauser, Marco Herling, Oleksandra Skorobohatko, Nimitha Mathew, Cornelius Schmidt, Claudius Klein, Marie Follo, Christine Dierks
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引用次数: 0

Abstract

Inhibition of the proximal B cell receptor (BCR) signaling pathway by BTK inhibitors is highly effective in the treatment of CLL, but drug resistance or intolerance occurs. Here, we investigated c-Jun N-terminal protein kinase 1 (JNK1) as an alternative drug target in the distal BCR pathway. JNK1 was preferentially overexpressed and activated in poor prognostic CLL with unmutated IGHV. Proximal BCR inhibition (BTK, PI3K, or SYK inhibitors) or SYK knockdown efficiently dephosphorylated JNK1, identifying JNK1 as a critical BCR downstream kinase in CLL. JNK1 inhibition induced apoptosis in primary CLL cells, resulting in the downregulation of BCL2, MCL1, and c-JUN. JNK1 inhibition in patient-derived CLL xenografted mice and Eµ-TCL1-tg mice prevented CLL progression, reduced splenic infiltration, and restored T cell function and normal hematopoiesis. JNK1 inhibitors even remained effective in ibrutinib refractory CLL. In conclusion, our study revealed JNK1 as a promising drug target in CLL downstream of the BCR, overcoming ibrutinib resistance, blocking the protective microenvironment, and improving CLL-specific immunosuppressive mechanisms.

JNK1 抑制剂可靶向远端 B 细胞受体信号转导,克服 CLL 中 BTK 抑制剂的耐药性。
BTK抑制剂抑制近端B细胞受体(BCR)信号通路对治疗CLL非常有效,但耐药性或不耐受性时有发生。在此,我们将c-Jun N-末端蛋白激酶1(JNK1)作为BCR远端通路的替代药物靶点进行了研究。在IGHV未突变的预后不良CLL中,JNK1优先过表达并被激活。近端BCR抑制剂(BTK、PI3K或SYK抑制剂)或SYK敲除能有效地使JNK1去磷酸化,从而确定JNK1是CLL中关键的BCR下游激酶。抑制 JNK1 可诱导原代 CLL 细胞凋亡,导致 BCL2、MCL1 和 c-JUN 下调。在源自患者的 CLL 异种移植小鼠和 Eµ-TCL1-tg 小鼠中抑制 JNK1 可阻止 CLL 的发展,减少脾脏浸润,恢复 T 细胞功能和正常造血功能。JNK1 抑制剂甚至对伊布替尼难治性 CLL 仍然有效。总之,我们的研究揭示了JNK1是BCR下游CLL的一个有前景的药物靶点,它能克服伊布替尼耐药,阻断保护性微环境,改善CLL特异性免疫抑制机制。
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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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