Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA756171 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15524787_1.fastq.gz | Fastqsanger.gz | |||
| SRR15524787_2.fastq.gz | Fastqsanger.gz | |||
| SRR15524788_1.fastq.gz | Fastqsanger.gz | |||
| SRR15524788_2.fastq.gz | Fastqsanger.gz | |||
| SRR15524789_1.fastq.gz | Fastqsanger.gz |
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Project description:BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL1 are in clinical trials. Yet, drug resistance eventually ensues, highlighting the urgency to understand the underlying mechanisms. Our genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy regulators sensitizes AML to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), a GTPase that controls mitochondrial dynamics and the degradation of damaged mitochondria through mitophagy. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. MFN2 inactivation, using a novel small molecule inhibitor, and pharmacologic inhibition of mitophagy synergizes with BH3 mimetics. Overall, targeting of mitophagy along with BCL2-family members is a promising strategy to overcome drug resistance in AML.
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Project description:De novo purine synthesis is required to promote tumor growth; however, its role in therapy resistance remains elusive. Here, through a dynamic BH3-priming based CRISPR-Cas9 screen, we found that deletion of ADSS2, which encodes for an enzyme functioning in de novo AMP synthesis, re-sensitizes drug resistant acute myeloid leukemia (AML) cells to BH3 mimetics. Single-cell sequencing and metabolomics analyses reveal that high ADSS2 activity in leukemia samples including those with TP53 aberrations inversely correlates with venetoclax responsiveness. Further, we developed anADSS2 antagonist, exhibiting synergism with BH3 mimetics in preclinical AML models. Mechanistically, sensitization to BH3 mimetics mediated by ADSS targeting was associated with downregulated AMPK activity, which governs mitochondrial homeostasis. AMPK activity in resistant cells promotes mitophagy to eliminate damaged mitochondria upon BH3 mimetics treatment. These data demonstrate that AMP synthesis governs venetoclax resistance, and that combining ADSS targeting with BH3 mimetic treatment could represent a promising approach against AML.
2025-11-21 | GSE280009 | GEO
Project description:De novo purine synthesis is required to promote tumor growth; however, its role in therapy resistance remains elusive. Here, through a dynamic BH3-priming based CRISPR-Cas9 screen, we found that deletion of ADSS2, which encodes for an enzyme functioning in de novo AMP synthesis, re-sensitizes drug resistant acute myeloid leukemia (AML) cells to BH3 mimetics. Single-cell sequencing and metabolomics analyses reveal that high ADSS2 activity in leukemia samples including those with TP53 aberrations inversely correlates with venetoclax responsiveness. Further, we developed anADSS2 antagonist, exhibiting synergism with BH3 mimetics in preclinical AML models. Mechanistically, sensitization to BH3 mimetics mediated by ADSS targeting was associated with downregulated AMPK activity, which governs mitochondrial homeostasis. AMPK activity in resistant cells promotes mitophagy to eliminate damaged mitochondria upon BH3 mimetics treatment. These data demonstrate that AMP synthesis governs venetoclax resistance, and that combining ADSS targeting with BH3 mimetic treatment could represent a promising approach against AML.
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Project description:BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3 mimetics in AML. Insensitivity to BH3 mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux, which acts as a prosurvival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3 mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.SignificanceAML remains one of the most difficult-to-treat blood cancers. BH3 mimetics represent a promising therapeutic approach to eliminate AML blasts by activating the apoptotic pathway. Enhanced mitochondrial clearance drives resistance to BH3 mimetics and predicts poor prognosis. Reverting excessive mitophagy can halt BH3-mimetic resistance in AML. This article is highlighted in the In This Issue feature, p. 1501.
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Project description:Inhibition of ADSS2-mediated de novo AMP biosynthesis resensitizes acute myeloid leukemia to BH3 mimetics
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Project description:Inhibition of ADSS2-mediated de novo AMP biosynthesis resensitizes acute myeloid leukemia to BH3 mimetics [scRNA-seq]
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Project description:Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC). Despite the good initial responses, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), activation of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve and paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced the potency of BV6, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance
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Project description:TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed TP53-mutant mouse B lymphoma, human NK/T lymphoma and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
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