Open AccessThe ClpP activator ONC‐212 (TR‐31) inhibits BCL2 and B‐cell receptor signaling in CLL
Author(s) -
Fatima Narjis,
Shen Yandong,
Crassini Kyle,
Iwanowicz Edwin J.,
Lang Henk,
Karanewsky Donald S.,
Christopherson Richard I.,
Mulligan Stephen P.,
Best Oliver G.
Publication year - 2021
Publication title -
ejhaem
Language(s) - English
Resource type - Journals
ISSN - 2688-6146
DOI - 10.1002/jha2.160
Subject(s) - chronic lymphocytic leukemia , mcl1 , cancer research , breakpoint cluster region , apoptosis , protein kinase b , signal transduction , biology , venetoclax , mapk/erk pathway , receptor , leukemia , medicine , immunology , microbiology and biotechnology , downregulation and upregulation , genetics , gene
Despite advances in therapy, a significant proportion of patients with chronic lymphocytic leukemia (CLL) relapse with drug resistant disease. Novel treatment approaches are required, particularly for high risk disease. The imipridones represent a new class of cancer therapy that has been investigated in pre‐clinical and clinical trials against a range of different cancers. We investigated the effects of the imipridone, ONC‐212, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment and a TP53 ko CLL cell line (OSU‐CLL‐ TP53 ko). ONC‐212 induced dose‐dependent apoptosis, cell cycle arrest and reduced the migration of CLL cells in vitro, including cells from patients with TP53 lesions and OSU‐CLL‐ TP53 ko cells. The effects of ONC‐212 were associated with protein changes consistent with activation of the mitochondrial protease, CIpP, and the integrated stress response. We also observed inhibition of pathways downstream of the B‐cell receptor (BCR) (AKT and MAPK‐ERK1/2) and a pro‐apoptotic shift in the balance of proteins of the BCL2 family of proteins (BCL2, MCL1, BCLxL, BAX and NOXA). In conclusion, the study suggests ONC‐212 may represent an effective treatment for high risk CLL disease by inhibiting multiple facets of the BCR signaling pathway and the pro‐survival effects of the BCL2‐family proteins.