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

Abstract

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.

• Authors: Mathilde Rikje Willemijn de Jong, Myra Langendonk, Bart Reitsma, Marcel Nijland, Anke van den Berg, Emanuele Ammatuna, Lydia Visser, Tom van Meerten
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 23 (Nov 30 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31801186 (Publication Type: Journal Article)

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• BCL2 protein, human
• BCL2L1 protein, human
• Bcl-2-Like Protein 11
• Bridged Bicyclo Compounds, Heterocyclic
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Pyrimidines
• R-CHOP protocol
• S63845
• Sulfonamides
• Thiophenes
• bcl-X Protein
• Rituximab
• Vincristine
• Doxorubicin
• Cyclophosphamide
• venetoclax
• Prednisone
• navitoclax

Topics

• Aniline Compounds (pharmacology)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bcl-2-Like Protein 11 (genetics, metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclophosphamide (therapeutic use)
• Doxorubicin (therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics, metabolism, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics, metabolism)
• Prednisone (therapeutic use)
• Prognosis
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology)
• Rituximab (therapeutic use)
• Signal Transduction
• Sulfonamides (pharmacology)
• Thiophenes (pharmacology)
• Treatment Outcome
• Vincristine (therapeutic use)
• bcl-X Protein (antagonists & inhibitors, genetics, metabolism)