TY - JOUR
T1 - CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma
AU - Mohanty, Atish
AU - Sandoval, Natalie
AU - Das, Manasi
AU - Pillai, Raju
AU - Chen, Lu
AU - Chen, Robert W.
AU - Amin, Hesham M.
AU - Wang, Michael
AU - Marcucci, Guido
AU - Weisenburger, Dennis D.
AU - Rosen, Steven T.
AU - Pham, Lan V.
AU - Ngo, Vu N.
N1 - Funding Information:
We thank Drs. John Chan for helpful discussion and Craig Thomas for research reagents. This work was supported in part by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. D.D.W is supported by NIH/NCI grant 5U01CA62505-19. V.N.N. is supported by the American Hematology Society and the Gabrielle's Angel Foundation for Cancer Research.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Ibrutinib resistance
KW - Mantle cell lymphoma
KW - Somatic mutations
KW - cyclin D1
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U2 - 10.18632/oncotarget.12434
DO - 10.18632/oncotarget.12434
M3 - Article
C2 - 27713153
AN - SCOPUS:84995756384
SN - 1949-2553
VL - 7
SP - 73558
EP - 73572
JO - Oncotarget
JF - Oncotarget
IS - 45
ER -