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CDK6 kinase inhibition opens up metabolic dependencies in BCR-ABL+ leukemia

ABSTRACT: CDK6 kinase inhibition opens up metabolic dependencies in BCR-ABL+ leukemia

PROVIDER: PRJNA1113623 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29089339.fastq.gz	Fastqsanger.gz
	SRR29089340.fastq.gz	Fastqsanger.gz
	SRR29089341.fastq.gz	Fastqsanger.gz
	SRR29089342.fastq.gz	Fastqsanger.gz
	SRR29089343.fastq.gz	Fastqsanger.gz

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CDK6 kinase inhibition opens up metabolic dependencies in BCR-ABL+ leukemia

Project description:Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. We here investigate the role of the cell cycle kinase CDK6 in the regulation of cellular energetics in BCR-ABL+ leukemia. Gene expression data and ChIP-Seq analysis from murine BCR-ABL+ cell lines expressing kinase-inactive CDK6 or no CDK6 highlight an activating role for the kinase in regulating the oxidative phosphorylation gene set by interacting with respective promoter regions. Our data imply a competition of CDK6 and Nrf-1, a master regulator of genes required for mitochondrial respiration, at the same sites. In line, cells expressing kinase- inactive CDK6 show signs of a defective electron transport chain and morphologically changed mitochondria. An enhanced cytoplasm/mitochondria ATP ratio together with high levels of pyruvate and lactate point towards a metabolic switch to glycolysis in those cells. Combinatorial treatment of BCR-ABL+ cell lines with the clinically used CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglocose (2-DG) reduced proliferation and led to enhanced apoptosis compared to single-agent treatments. Our data, suggest a new therapeutic avenue for hematologic malignancies with high CDK6 expression.

2025-02-26 | GSE267912 | GEO

Gene expression profiling of murine BCR-ABL+ CDK6-wt and CDK6-KO cells

Project description:Dertermination of chromatin accessibility in murine BCR-ABL+ CDK6-wt and CDK6-KO cells

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Gene expression profiling of murine BCR-ABL(p185)-positive CDK6-WT, CDK6-K43M and CDK6-KO cells

Project description:The aim of this experiment was to study the effects of a kinase-dead mutant of the cell cycle kinase CDK6 (CDK6-K43M) on gene expression in a murine model of BCR-ABL driven leukemia.

2025-02-26 | GSE266394 | GEO

ChIP seq of CDK6-WT and CDK6-K43M in murine BCR-ABL(p185)+ pre/pro B-cells

Project description:The aim of this experiment was to study the DNA interaction of a kinase-dead mutant of the cell cycle kinase CDK6 (CDK6-K43M) in a murine model of BCR-ABL driven leukemia.

2024-06-30 | GSE264219 | GEO

C-JUN promotes BCR-ABL induced lymphoid leukemia by inhibiting methylation of the 5´ region of Cdk6

Project description:The transcription factor c-JUN and its upstream kinase JNK1 have been implicated in BCR-ABL induced leukemogenesis. JNK1 has been shown to regulate BCL2 expression thereby altering leukemogenesis, but the impact of c-JUN remained unclear. In this study we show that JNK1 and c-JUN promote leukemogenesis via separate pathways, since lack of c-JUN impairs proliferation of p185BCR-ABL transformed cells without affecting viability. The decreased proliferation of c-JunD/D cells is associated with the loss of cyclin dependent kinase 6 (CDK6) expression. In c-JunD/D cells CDK6 expression becomes down-regulated upon BCR-ABL induced transformation which correlates with CpG island methylation within the 5´ region of Cdk6. We verified the impact of Cdk6 deficiency by using Cdk6-/- mice that developed BCR-ABL induced B-lymphoid leukemia with significantly increased latency and an attenuated disease phenotype. In addition we show that re-expression of CDK6 in BCR-ABL transformed c-JunD/D cells reconstitutes proliferation and tumor formation in Nu/Nu mice. In summary, our study reveals a novel function for the AP-1 transcription factor c-JUN in leukemogenesis by antagonizing promoter methylation. Moreover, we identify CDK6 as relevant and critical target of AP-1 regulated DNA methylation upon BCR-ABL induced transformation, thereby accelerating leukemogenesis.

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C-JUN promotes BCR-ABL induced lymphoid leukemia by inhibiting methylation of the 5´ region of Cdk6

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ATAC seq in murine BCR-ABL(p185)-positive pre/pro B-cells expressing wildtype CDK6 or a kinase-dead mutant (CDK6 K43M)

Project description:The aim of this experiment was to study the chromatin accessibility in BCR-ABL(p185)-positive pre/pro B-cells expressing wildtype CDK6 or a kinase-dead mutant (CDK6 K43M)

2025-02-26 | GSE266393 | GEO

Gene expression profiling of murine BCR-ABL+ CDK6-wt and CDK6-KO cells

Project description:Gene expression profiling of murine BCR-ABL+ CDK6-wt and CDK6-KO cells

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Expression profile of BCR-ABL+ colonies, isolated from methylcellulose

Project description:BCR-ABL was used to transform Cdk6+/+, Cdk6-K43M or Cdk6-/- bone marrow cells. RNA was isolated from individual colonies formed in methylcellulose at day 10 post-transduction

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Gene expression profiling of murine BCR-ABL(p185)-positive CDK6-WT, CDK6-K43M and CDK6-KO cells

Project description:Gene expression profiling of murine BCR-ABL(p185)-positive CDK6-WT, CDK6-K43M and CDK6-KO cells

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