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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 E\u00b5-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.<\/jats:p>","DOI":"10.1084\/jem.20230681","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T02:20:42Z","timestamp":1720491642000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5937-6764","authenticated-orcid":true,"given":"Shifa Khaja","family":"Saleem","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vzbgh69","id-type":"ROR","asserted-by":"publisher"}],"name":"Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg 1 Department 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