Open AccessPF521 CHOP TREATMENT ENHANCES DEPENDENCY ON BCL‐2, MCL‐1 AND BCL‐XL IN DIFFUSE LARGE B‐CELL LYMPHOMA
Author(s) -
De Jong M.,
Langendonk M.,
Reitsma B.,
Nijland M.,
Huls G.,
Berg A.,
Ammatuna E.,
Visser L.,
Meerten T.
Publication year - 2019
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/01.hs9.0000560180.55550.9c
Subject(s) - chop , diffuse large b cell lymphoma , vincristine , cancer research , lymphoma , doxorubicin , rituximab , venetoclax , medicine , gene expression profiling , oncology , biology , cyclophosphamide , chemotherapy , gene expression , leukemia , chronic lymphocytic leukemia , gene , biochemistry
Background: Deregulation of anti‐apoptotic proteins BCL‐2, MCL‐1, BCL‐XL or BCL‐W is often a contributing factor to oncogenic transformation or progression, including in diffuse large B‐cell lymphoma (DLBCL). Gene expression profiling and immunohistochemistry analysis has shown overexpression of BCL‐2 in DLBCL is an important adverse prognostic factor, and has been correlated to resistance of standard therapy composed of cyclophosphamide, vincristine, doxorubicin, prednisolone and the anti‐CD20 antibody rituximab (R‐CHOP). Although these studies show a clear relation between BCL‐2 and therapy response, at the moment it remains unclear what the effect is of CHOP therapy on the intracellular anti‐apoptotic dependency in DLBCL. Aims: Here, we aim to determine the effect of CHOP treatment on the anti‐apoptotic proteins by employing BH3 profiling and investigate whether CHOP treatment enhances sensitivity for BH3 mimetic drugs. Methods: We first investigated the predictive value of anti‐apoptotic gene expression in 1800 DLBCL patients treated with CHOP or R‐CHOP. Next, dynamic BH3 profiles were acquired for 8 DLBCL cell lines treated with CHOP for 18 hours. Validation experiments were performed for CHOP combined with BH3 mimetic drugs on selected DLBCL cell lines. Finally, individual CHOP components were tested using BH3 profiling. Results: Gene expression analysis of anti‐apoptotic proteins revealed BCL‐2 had a significant negative association with survival in DLBCL patients, which was not observed for MCL‐1, BCL‐XL or BCL‐W. Analysis of anti‐apoptotic proteins expression in DLBCL cell lines demonstrated a strong adverse correlation for BCL‐2 protein expression and venetoclax (BCL‐2i) sensitivity, and a strong positive correlation for BCL‐2 protein expression and CHOP sensitivity. Dynamic BH3 profiling of CHOP‐treated DLBCL cell lines showed CHOP was able to enhance dependency on MCL‐1, BCL‐XL and BCL‐2. Validation experiments with BH3 mimetic drugs confirmed cell line specific enhanced sensitivity for S63845 (MCL‐1i), venetoclax (BCL‐2i) and/or navitoclax (BCL‐2/BCL‐XL/BCL‐Wi). No sensitivity‐related changes were observed on anti‐apoptotic protein expression after CHOP treatment. Dynamic BH3 analysis of single CHOP components revealed doxorubicin and vincristine were able to induce changes that were similar to the dynamic CHOP‐treated profiles. Summary/Conclusion: Gene expression analysis confirm that BCL‐2 status is a treatment‐independent predictive factor for DLBCL survival. However, our results demonstrate that CHOP treatment also induces cell‐specific increased anti‐apoptotic dependency on MCL‐1 or BCL‐XL, and not just BCL‐2. These results provide new perspective for the treatment of CHOP‐resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcome.