Acquired MYC rearrangement potentially associated with ibrutinib resistance in mantle cell lymphoma

Mantle 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.