Yuan, Chang-TsuChang-TsuYuanSun, Li-YuLi-YuSunCheng, Chieh-LungChieh-LungChengYao, MingMingYaoKo, Bor-ShengBor-ShengKoWEI-LI MA2026-03-232026-03-232025-12-04https://scholars.lib.ntu.edu.tw/handle/123456789/736521Mantle cell lymphoma (MCL) is a subtype of mature B-cell lymphoma characterized by the expression of CD5, cyclin D1, and SOX11, along with the IGH::CCND1 rearrangement. While the introduction of ibrutinib, a Bruton tyrosine kinase inhibitor, has significantly improved outcomes, resistance remains a challenge. The role of MYC rearrangement in ibrutinib resistance remains unclear. We investigated the pathological features and the status of MYC, BCL2, and BCL6 rearrangements in ibrutinib-resistant versus ibrutinib-responsive MCL tumors. Among the 31 specimens from 27 patients, 7 tumors (23%) were resistant to ibrutinib. A comparison between ibrutinib-resistant and ibrutinib-responsive tumors revealed a significant difference in c-Myc expression (median 25 vs. 5%, p = 0.008) and MYC rearrangement (43 [3/7] vs. 0% [0/23], p = 0.009). All MYC rearrangements were acquired, and these tumors demonstrated intrinsic resistance to ibrutinib. Furthermore, MYC-rearranged tumors exhibited blastoid or pleomorphic cytomorphology, CD10 expression, elevated c-Myc expression, and a high Ki-67 proliferative index. In conclusion, our findings suggest that c-Myc overexpression and MYC rearrangement are associated with ibrutinib resistance in MCL. Detecting MYC rearrangement in selected MCL cases could be critical for optimizing treatment strategies and improving patient outcomes.enBCL2 rearrangementBCL6 rearrangementMYC rearrangementDouble-hitIbrutinib resistanceMantle cell lymphomajournal article10.1007/s00428-025-04364-341339992