CD79B limits response of diffuse large B cell lymphoma to ibrutinib

Abstract

Blockage of B cell receptor signaling with ibrutinib presents a promising clinical approach for treatment of B-cell malignancies. However, many patients show primary resistance to the drug or develop secondary resistance. In the current study, cDNA microarray and Western blot analyses revealed CD79B upregulation in the activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) that display differential resistance to ibrutinib. CD79B overexpression was sufficient to induce resistance to ibrutinib and enhanced AKT and MAPK activation, indicative of an alternative mechanism underlying resistance. Conversely, depletion of CD79B sensitized primary refractory cells to ibrutinib and led to reduced phosphorylation of AKT or MAPK. Combination of the AKT inhibitor or the MAPK inhibitor with ibrutinib resulted in circumvention of both primary and acquired resistance in ABC-DLBCL. Our data collectively indicate that CD79B overexpression leading to activation of AKT/MAPK is a potential mechanism underlying primary ibrutinib resistance in ABC-DLBCL, and support its utility as an effective biomarker to predict therapeutic response to ibrutinib.

Keywords:

• CD79B
• AKT
• MAPK
• ibrutinib resistance
• DLBCL

Acknowledgements

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2014R1A2A1A11052626).

Authorship

Contribution: J.K. performed the research and analyzed the data; C.P. and W.S.K. designed the research and analyzed the data; K.R. and S.J.K. assisted with preparation of patient-derived primary human ABC-DLBCL; J.K. and C.P. wrote the paper; and C.P. and W.S.K. supervised the work.

Potential conflict of interest

The authors declare no competing financial interests.

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2015.1113276.