Inhibition of MCL1 induces apoptosis in anaplastic large cell lymphoma and in primary effusion lymphoma.

Abstract

Overexpression of antiapoptotic BCL2 family proteins occurs in various hematologic malignancies and contributes to tumorigenesis by inhibiting the apoptotic machinery of the cells. Antagonizing BH3 mimetics provide an option for medication, with venetoclax as the first drug applied for chronic lymphocytic leukemia and for acute myeloid leukemia. To find additional hematologic entities with ectopic expression of BCL2 family members, we performed expression screening of cell lines applying the LL-100 panel. Anaplastic large cell lymphoma (ALCL) and primary effusion lymphoma (PEL), 2/22 entities covered by this panel, stood out by high expression of MCL1 and low expression of BCL2. The MCL1 inhibitor AZD-5991 induced apoptosis in cell lines from both malignancies, suggesting that this BH3 mimetic might be efficient as drug for these diseases. The ALCL cell lines also expressed BCLXL and BCL2A1, both contributing to survival of the cells. The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/mTOR inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, offering an alternative to avoid thrombocytopenia which is associated with the use of BCLXL inhibitors.

• Authors: Hilmar Quentmeier, Robert Geffers, Vivien Hauer, Stefan Nagel, Claudia Pommerenke, Cord C Uphoff, Margarete Zaborski, Hans G Drexler
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 1085 (01 20 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35058488 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• AZD5991
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Bax protein (53-86)
• Imidazoles
• MCL1 protein, human
• Macrocyclic Compounds
• Myeloid Cell Leukemia Sequence 1 Protein
• Peptide Fragments
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Quinolines
• dactolisib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Cell Line, Tumor
• Gene Expression (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Imidazoles (pharmacology)
• Lymphoma, Large-Cell, Anaplastic (drug therapy, genetics, metabolism)
• Lymphoma, Primary Effusion (drug therapy, genetics, metabolism)
• Macrocyclic Compounds (pharmacology)
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics, metabolism)
• Peptide Fragments (metabolism, pharmacology)
• Proto-Oncogene Proteins (metabolism, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, genetics, metabolism)
• Quinolines (pharmacology)