Cargando…
DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation
SIMPLE SUMMARY: Poor response to venetoclax in TP53-mutated (TP53mut) acute myeloid leukemia (AML) is a clinical challenge. To develop more effective therapeutic strategies for this subset of AML with dismal prognosis, the molecular mechanism involved in the development of venetoclax resistance need...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913445/ https://www.ncbi.nlm.nih.gov/pubmed/36765703 http://dx.doi.org/10.3390/cancers15030745 |
_version_ | 1784885429197078528 |
---|---|
author | Jang, Ji Eun Hwang, Doh Yu Eom, Ju-In Cheong, June-Won Jeung, Hoi-Kyung Cho, Hyunsoo Chung, Haerim Kim, Jin Seok Min, Yoo Hong |
author_facet | Jang, Ji Eun Hwang, Doh Yu Eom, Ju-In Cheong, June-Won Jeung, Hoi-Kyung Cho, Hyunsoo Chung, Haerim Kim, Jin Seok Min, Yoo Hong |
author_sort | Jang, Ji Eun |
collection | PubMed |
description | SIMPLE SUMMARY: Poor response to venetoclax in TP53-mutated (TP53mut) acute myeloid leukemia (AML) is a clinical challenge. To develop more effective therapeutic strategies for this subset of AML with dismal prognosis, the molecular mechanism involved in the development of venetoclax resistance needs to be elucidated. To the best of our knowledge, this study is the first to demonstrate that DRP1, a key player in the regulation of mitochondrial fission, is functionally involved in the development of venetoclax resistance in TP53mut AML. Inhibition of DRP1 with Mdivi-1 led to enhanced mitochondria-mediated cell death with the upregulation of BAX/BAK in TP53mut leukemia cell lines and primary leukemic blasts obtained from patients with TP53mut AML. Anti-apoptotic molecules, such as MCL-1 and BCL-xL, were reduced after combination treatment with venetoclax and Mdivi-1. These findings suggest that the combination of venetoclax with pharmacological DRP1 inhibition needs to be clinically evaluated for TP53mut AML. ABSTRACT: Although TP53 mutations in acute myeloid leukemia (AML) are associated with poor response to venetoclax, the underlying resistance mechanism remains unclear. Herein, we investigated the functional role of dynamin-related protein 1 (DRP1) in venetoclax sensitivity in AML cells with respect to TP53 mutation status. Effects of DRP1 inhibition on venetoclax-induced cell death were compared in TP53-mutated (THP-1 and Kasumi-1) and TP53 wild-type leukemia cell lines (MOLM-13 and MV4-11), as well as in primary AML cells obtained from patients. Venetoclax induced apoptosis in TP53 wild-type AML cells but had limited effects in TP53-mutated AML cells. DRP1 expression was downregulated in MOLM-13 cells after venetoclax treatment but was unaffected in THP-1 cells. Cotreatment of THP-1 cells with venetoclax and a TP53 activator NSC59984 downregulated DRP1 expression and increased apoptosis. Combination treatment with the DRP1 inhibitor Mdivi-1 and venetoclax significantly increased mitochondria-mediated apoptosis in TP53-mutated AML cells. The combination of Mdivi-1 and venetoclax resulted in noticeable downregulation of MCL-1 and BCL-xL, accompanied by the upregulation of NOXA, PUMA, BAK, and BAX. These findings suggest that DRP1 is functionally associated with venetoclax sensitivity in TP53-mutated AML cells. Targeting DRP1 may represent an effective therapeutic strategy for overcoming venetoclax resistance in TP53-mutated AML. |
format | Online Article Text |
id | pubmed-9913445 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99134452023-02-11 DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation Jang, Ji Eun Hwang, Doh Yu Eom, Ju-In Cheong, June-Won Jeung, Hoi-Kyung Cho, Hyunsoo Chung, Haerim Kim, Jin Seok Min, Yoo Hong Cancers (Basel) Article SIMPLE SUMMARY: Poor response to venetoclax in TP53-mutated (TP53mut) acute myeloid leukemia (AML) is a clinical challenge. To develop more effective therapeutic strategies for this subset of AML with dismal prognosis, the molecular mechanism involved in the development of venetoclax resistance needs to be elucidated. To the best of our knowledge, this study is the first to demonstrate that DRP1, a key player in the regulation of mitochondrial fission, is functionally involved in the development of venetoclax resistance in TP53mut AML. Inhibition of DRP1 with Mdivi-1 led to enhanced mitochondria-mediated cell death with the upregulation of BAX/BAK in TP53mut leukemia cell lines and primary leukemic blasts obtained from patients with TP53mut AML. Anti-apoptotic molecules, such as MCL-1 and BCL-xL, were reduced after combination treatment with venetoclax and Mdivi-1. These findings suggest that the combination of venetoclax with pharmacological DRP1 inhibition needs to be clinically evaluated for TP53mut AML. ABSTRACT: Although TP53 mutations in acute myeloid leukemia (AML) are associated with poor response to venetoclax, the underlying resistance mechanism remains unclear. Herein, we investigated the functional role of dynamin-related protein 1 (DRP1) in venetoclax sensitivity in AML cells with respect to TP53 mutation status. Effects of DRP1 inhibition on venetoclax-induced cell death were compared in TP53-mutated (THP-1 and Kasumi-1) and TP53 wild-type leukemia cell lines (MOLM-13 and MV4-11), as well as in primary AML cells obtained from patients. Venetoclax induced apoptosis in TP53 wild-type AML cells but had limited effects in TP53-mutated AML cells. DRP1 expression was downregulated in MOLM-13 cells after venetoclax treatment but was unaffected in THP-1 cells. Cotreatment of THP-1 cells with venetoclax and a TP53 activator NSC59984 downregulated DRP1 expression and increased apoptosis. Combination treatment with the DRP1 inhibitor Mdivi-1 and venetoclax significantly increased mitochondria-mediated apoptosis in TP53-mutated AML cells. The combination of Mdivi-1 and venetoclax resulted in noticeable downregulation of MCL-1 and BCL-xL, accompanied by the upregulation of NOXA, PUMA, BAK, and BAX. These findings suggest that DRP1 is functionally associated with venetoclax sensitivity in TP53-mutated AML cells. Targeting DRP1 may represent an effective therapeutic strategy for overcoming venetoclax resistance in TP53-mutated AML. MDPI 2023-01-25 /pmc/articles/PMC9913445/ /pubmed/36765703 http://dx.doi.org/10.3390/cancers15030745 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jang, Ji Eun Hwang, Doh Yu Eom, Ju-In Cheong, June-Won Jeung, Hoi-Kyung Cho, Hyunsoo Chung, Haerim Kim, Jin Seok Min, Yoo Hong DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation |
title | DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation |
title_full | DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation |
title_fullStr | DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation |
title_full_unstemmed | DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation |
title_short | DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation |
title_sort | drp1 inhibition enhances venetoclax-induced mitochondrial apoptosis in tp53-mutated acute myeloid leukemia cells through bax/bak activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913445/ https://www.ncbi.nlm.nih.gov/pubmed/36765703 http://dx.doi.org/10.3390/cancers15030745 |
work_keys_str_mv | AT jangjieun drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT hwangdohyu drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT eomjuin drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT cheongjunewon drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT jeunghoikyung drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT chohyunsoo drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT chunghaerim drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT kimjinseok drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation AT minyoohong drp1inhibitionenhancesvenetoclaxinducedmitochondrialapoptosisintp53mutatedacutemyeloidleukemiacellsthroughbaxbakactivation |