Acquired MYC rearrangement potentially associated with ibrutinib resistance in mantle cell lymphoma.
Journal
Virchows Archiv : an international journal of pathology
ISSN
1432-2307
Date Issued
2025-12-04
Author(s)
Abstract
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.
Subjects
BCL2 rearrangement
BCL6 rearrangement
MYC rearrangement
Double-hit
Ibrutinib resistance
Mantle cell lymphoma
Type
journal article