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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): B-cell Acute Lymphoblastic Leukemia

SUBMITTER: Dhoyazan Azazi

LAB HEAD: Brian J.P. Huntly

PROVIDER: PXD061362 | Pride | 2025-05-01

REPOSITORIES: Pride

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			Action	DRS
	Lumos_06022023_PR1627_JOK_FR.msf	Msf
	Lumos_06022023_PR1627_JOK_FR01.raw	Raw
	Lumos_06022023_PR1627_JOK_FR02.raw	Raw
	Lumos_06022023_PR1627_JOK_FR03.raw	Raw
	Lumos_06022023_PR1627_JOK_FR04.raw	Raw

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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.

2025-03-26 | GSE289012 | GEO

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

2025-03-26 | GSE289011 | GEO

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

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.

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Asparagine bioavailability governs metastasis in a model of breast cancer

Project description:Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites1. A combination of differential expression and focused in vitro and in vivo RNAi screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, Asparagine Synthetase (ASNS) expression in a patient’s primary tumour was most strongly correlated with later metastatic relapse. Here, we have shown that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by Asns knockdown, treatment with L-asparaginase, or dietary asparagine restriction reduced metastasis without impacting growth of the primary tumour, whereas increased dietary asparagine or enforced Asns expression promoted metastatic progression. Altering asparagine availability in vitro strongly influenced invasive potential, and this was correlated with an impact on proteins that promote the epithelial to mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.

2018-02-07 | PXD008805 | Pride

Ribosome biogenesis factors are post-transcriptionally depleted in NPM1-mutant acute myeloid leukemia and can be targeted therapeutically

Project description:Mutations in the NPM1 gene are found in more than 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal (NoLS) and create a novel nuclear export signal (NES), leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first examine the effects of isolated NPM1c mutations on the global proteome of pre-leukemic hematopoietic stem and progenitor cells (HSPCs) using conditional knock-in Npm1cA/+ mice. We discovered that many proteins involved in ribosome biogenesis are significantly depleted in these HSPCs, but also importantly in human NPM1-mutant AMLs. In line with this, we found that pre-leukemic Npm1cA/+ HSPCs display higher sensitivity to RNA pol I inhibitors, including Actinomycin D (ActD), compared to Npm1+/+ cells. Combination treatment with ActD and Venetoclax inhibited the growth and colony forming ability of pre-leukemic and leukemic NPM1c+ cells and low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Furthermore, using data from CRISPR drop-out screens, we identified and validated TSR3, a 40S ribosomal maturation factor whose knock-out preferentially inhibited the proliferation of NPM1c+ AML cells by activating a p53-dependent apoptotic response. Similarly to low-dose ActD treatment, TSR3 depletion could partially restore sensitivity to Venetoclax in therapy-resistant NPM1c+ AML models.

2025-05-27 | PXD053249 | Pride

CREBBP is a novel tumour suppressor in solid tumours

Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.

2022-03-23 | PXD012098 | Pride

Transcriptomic alterations in ferroptotic murine embryonic fibroblasts

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Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1

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