Abstract B11: Expression and functional analysis of aurora kinase A/B in double hit and triple hit B-cell lymphomas

Abstract

Abstract Background: Double-hit lymphoma (DHL) or triple-hit lymphoma (THL) is associated with translocations of MYC along with the genomic rearrangements of BCL-2 and BCL-6. MYC is demonstrated to upregulate Aurora kinase (AURK) A and B expression, which is implicated in MYC-driven lymphomagenesis. Although a novel AURK inhibitor MLN8237 showed promising treatment outcomes in a phase II clinical trial in patients with various lymphomas including B-cell lineage, expression patterns and functional inhibition of AURK A and B in DHL and THL remains to be determined. Methods: Expression patterns of AURK A and B proteins in DHL (15 BCL2+; 4 BCL6+ cases), THL (1 case) and reactive lymphoid hyperplasia were analyzed by IHC in formalin-fixed, paraffin-embedded tissues utilizing AURK A and B specific antibodies. Cases with strong nuclear staining in more than 30% of lymphoma cells were scored positive. Cell viability by MTS assays and apoptosis by flow cytometry were assessed in DoGKiT DHL cell line and CS-THL1 THL cell line at 72h post treatment with AURK inhibitor MLN8237 single or combination with DNA methyltransferase inhibitor, Decitabine (DAC), proteasome inhibitor, Bortezomib (BTZ) or classical chemotherapeutic agent, Doxorubicin (DOX). Results: All cases of DHL (19/19) showed nuclear positivity for AURK A and B; THL was AURK A reactive but AURK B noted only in 5% of the cells. AURK A expression in reactive hyperplasia was diffuse in germinal center cells (GCC) and AURK B had prominence in the dark zone of the GCC, but no significant expression seen in mantle or marginal zone cells. Combine exposure of MLN8237 with DAC, Bortezomib or DOX synergistically attenuated growth of DoGKiT and CS-THL1cells compare to single agent in vitro. Conclusion: AURK A and B expression is common in DHL and THL. AURK inhibitor exposure attenuated growth and induced apoptosis particularly in combination with DAC, BTZ and DOX. Thus, targeted therapy against AURK A and B should be considered in future clinical trials for the development of effective treatment modalities for DHL or THL. Note: This abstract was not presented at the conference. Citation Format: Munevver Cinar, Deniz Peker, Nalan Akyurek, Qin Huang, Jean Lopategui, Bekir Cinar, Serhan Alkan. Expression and functional analysis of aurora kinase A/B in double hit and triple hit B-cell lymphomas. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B11.