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Open AccessArticle

Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma

1
Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
2
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 6036; https://doi.org/10.3390/ijms20236036
Received: 15 November 2019 / Revised: 28 November 2019 / Accepted: 29 November 2019 / Published: 30 November 2019
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in DLBCL. Analysis of single CHOP compounds demonstrated that similar changes could also be induced by doxorubicin or vincristine, providing evidence for clinical combination therapies of doxorubicin or vincristine with BH3-mimetics in DLBCL. In conclusion, we show for the first time that CHOP treatment induces increased anti-apoptotic dependency on MCL-1 and BCL-XL, and not just BCL-2. These results provide new perspectives for the treatment of CHOP-resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcomes. View Full-Text
Keywords: diffuse large B-cell lymphoma; CHOP; BCL-2; MCL-1; BCL-XL; venetoclax; S63845 diffuse large B-cell lymphoma; CHOP; BCL-2; MCL-1; BCL-XL; venetoclax; S63845
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MDPI and ACS Style

de Jong, M.R.W.; Langendonk, M.; Reitsma, B.; Nijland, M.; van den Berg, A.; Ammatuna, E.; Visser, L.; van Meerten, T. Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma. Int. J. Mol. Sci. 2019, 20, 6036.

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