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Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition

ABSTRACT: Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition

PROVIDER: PRJNA1043135 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26891751_1.fastq.gz	Fastqsanger.gz
	SRR26891751_2.fastq.gz	Fastqsanger.gz
	SRR26891752_1.fastq.gz	Fastqsanger.gz
	SRR26891752_2.fastq.gz	Fastqsanger.gz
	SRR26891753_1.fastq.gz	Fastqsanger.gz

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Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition

Project description:We performed a targeted drug screen in isogenic human cell lines, identifying a number of actionable small molecules that specifically target CREBBP-mutated B-ALL. The most potent was the BCL2 inhibitor Venetoclax, which acts through a non-canonical mechanism resulting in ferroptotic cell death. CREBBP-mutated cell lines showed differences in cell-cycle, metabolism and response to oxidative stress. Lastly, we demonstrate that small-molecule inhibition of CREBBP sensitizes B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in-vitro and in-vivo, providing a potential novel drug combination for broader clinical translation in B-ALL.

2025-03-26 | GSE248265 | GEO

Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition

Project description:Performing a targeted drug-screen in isogenic human cell lines, we idenTfied a number of small molecules that specifically targeted CREBBP-mutated B-ALL, with the most potent the BCL2-inhibitor Venetoclax. Of note, this acted through a non-canonical mechanism resulTng in ferroptoTc rather than apoptoTc cell death. CREBBP-mutated cell lines showed differences in cell- cycle, metabolism, lipid composiTon and response to oxidaTve stress, predisposing them to ferroptosis, which were further dysregulated upon acquisiTon of Venetoclax resistance. Lastly, small- molecule inhibiTon of CREBBP pharmacocopies CREBBP-mutaTon, sensiTzing B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in-vitro and in-vivo, providing a potential novel drug combination for broader clinical translation in B-ALL.

2025-05-01 | PXD061362 | Pride

Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition [CUT&RUN]

Project description:Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition [CUT&RUN]

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Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition [ChIP-seq]

Project description:Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition [ChIP-seq]

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Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition [CUT&RUN]

Project description:B-cell acute lymphoblasTc leukemia (B-ALL) is a leading cause of death in childhood and outcomes in adults remain dismal. There is therefore an urgent clinical need for therapies that target the highest risk cases. MutaTons in the histone acetyltransferase CREBBP confer high-risk and increased chemoresistance in ALL. Performing a targeted drug-screen in isogenic human cell lines, we idenTfied a number of small molecules that specifically targeted CREBBP-mutated B-ALL, with the most potent the BCL2-inhibitor Venetoclax. Of note, this acted through a non-canonical mechanism resulTng in ferroptoTc rather than apoptoTc cell death. CREBBP-mutated cell lines showed differences in cell- cycle, metabolism, lipid composiTon and response to oxidaTve stress, predisposing them to ferroptosis, which were further dysregulated upon acquisiTon of Venetoclax resistance. Lastly, small- molecule inhibiTon of CREBBP pharmacocopies CREBBP-mutaTon, sensiTzing B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in-vitro and in-vivo, providing a potential novel drug combination for broader clinical translation in B-ALL.

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Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition [ChIP-seq]

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Ferroptotic Cell Death upon BCL2 Inhibition

Project description:B-cell acute lymphoblastic leukemia (B-ALL) is a leading cause of death in childhood and outcomes in adults remain dismal. There is therefore an urgent clinical need for therapies that target the highest risk cases. Mutations in the histone acetyltransferase CREBBP confer high-risk and increased chemoresistance in ALL. Performing a targeted drug-screen in isogenic human cell lines, we identified a number of small molecules that specifically targeted CREBBP-mutated B-ALL, with the most potent the BCL2-inhibitor Venetoclax. Of note, this acted through a non-canonical mechanism resulting in ferroptotic rather than apoptotic cell death. CREBBP-mutated cell lines showed differences in cell-cycle, metabolism, lipid composition and response to oxidative stress, predisposing them to ferroptosis, which were further dysregulated upon acquisition of Venetoclax resistance. Lastly, small-molecule inhibition of CREBBP pharmacocopies CREBBP-mutation, sensitizing B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in-vitro and in-vivo, providing a potential novel drug combination for broader clinical translation in B-ALL.

2025-04-01 | MSV000097461 | MassIVE

Crebbp deletion cooperates with Bcl2 over-expression to promote B-cell lymphoma in mice

Project description:We confirmed that common CREBBP mutations in human FL result in reduced acetyltransferase activity of the protein, and modeled this loss of function by B-cell-specific deletion of one or both alleles of Crebbp in transgenic mouse models. We show that Crebbp deletion results in deficits in B-cell development, and provide the first evidence from transgenic mouse models that Crebbp inactivation can cooperate with Bcl2 over-expression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B-cells we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the regulatory regions of these genes. In contrast, B-cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions that were enriched for Myc DNA binding motifs and Myc binding. These transgenic models therefore provide important links between Crebbp inactivation and Bcl2 dependence, and a potential role for Crebbp inactivation in the induction of Myc expression.

2017-06-01 | GSE85490 | GEO

Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax

Project description:Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as key challenge for cancer treatment. Recent studies have detected pervasive aberrant splicing in cancer cells, supporting its targeting for treatment of hematological malignancies.We here evaluated the expression of several spliceosome machinery components in primary multiple myeloma (MM) cells and the impact of splicing modulations on MM cell growth and viability.Our comprehensive gene expression analysis confirmed deregulation of spliceosome machinery components in MM cells compared to normal plasma cells (PCs) from healthy donors, while pharmacological and genetic modulation of splicing confirmed significant impact on growth and survival of MM cell lines and patient-derived malignant PCs. Transcriptomic analysis revealed deregulation of BCL2 family membersincluding decrease of proapoptotic long form of myeloid cell leukemia-1 (MCL1) expression in cells treated with splicing inhibitors. This caused a shift in the apoptotic priming resulting in improved BCL2-dependenceand increased sensitivity to Venetoclax, a BCL2 small molecule inhibitor, in vitro and in vivo. Overall, our data provide a rationale for supporting clinical use of splicing modulators as strategy to reprogram apoptotic dependencies, making MM patients more vulnerable to BCL2 inhibitors.

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