CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation, which leads to deregulated expression of the cell cycle regulatory protein cyclin D1 (CCND1). Genomic studies of MCL have also identified recurrent mutations in the coding region of CCND1. However, the functional consequence of these mutations is not known. Here, we showed that, compared to wild type (WT), single E36K, Y44D or C47S CCND1 mutations increased CCND1 protein levels in MCL cell lines. Mechanistically, these mutations stabilized CCND1 protein through attenuation of threonine-286 phosphorylation, which is important for proteolysis through the ubiquitin-proteasome pathway. In addition, the mutant proteins preferentially localized to the nucleus. Interestingly, forced expression of WT or mutant CCND1 increased resistance of MCL cell lines to ibrutinib, an FDA-approved Bruton tyrosine kinase inhibitor for MCL treatment. The Y44D mutant sustained the resistance to ibrutinib even at supraphysiologic concentrations (5–10 μM). Furthermore, primary MCL tumors with CCND1 mutations also expressed stable CCND1 protein and were resistant to ibrutinib. These findings uncover a new mechanism that is critical for the regulation of CCND1 protein levels, and is directly relevant to primary ibrutinib resistance in MCL.

Genetic landscape and deregulated pathways in B‐cell lymphoid malignancies

“…Recently, WES and RNA‐sequencing analysis revealed exon 1 CCND1 mutations in 14–34% of cases . These mutations lead to stabilized nuclear cyclin D1 protein , and have also been detected in 18% of the nnMCL subtype . Of interest, a small subset of SOX11‐positive MCL without the t(11;14) has been recognized (~5% of MCL), and more than half carry CCND2 gene rearrangements as alternative mechanism to CCND1 translocation .…”

Targeting of B‐cell receptor signalling in B‐cell malignancies

“…A novel mechanism of ibrutinib resistance in MCL may be through mutations of CCND1 . In vitro studies in cell lines and primary MCL cells have shown that CCND1 mutations increase the stability of CCND1 protein and cause ibrutinib resistance . More data on the mechanisms of resistance are expected to be gained from patients who are progressing on ibrutinib in the ongoing RAY trial.…”

Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma

“…Primary resistance to ibrutinib might be caused by diverse pathogenic mechanisms such as PIK3‐AKT pathway activation and activation of the NFkB pathways . Moreover, increased expression of cyclin D1 (CCND1) gene due to mutations or forced expression of the wild‐type gene could lead to increased resistance of MCL cell . In our patient, the immunohistochemistry showed that the expression of CCND1 was strongly positive at the start of the treatment with obinutuzumab and venetoclax.…”