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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE27028 | GEO | 2011/02/04

SECONDARY ACCESSION(S): PRJNA137685

REPOSITORIES: GEO

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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. Overall, 8 samples consisting of 4 wild type and 4 c-jun knock out samples were hybridized to MoGene-1_0-st-v1 microarrays.

2011-02-04 | E-GEOD-27028 | biostudies-arrayexpress

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

2020-11-24 | GSE156966 | GEO

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

2017-10-01 | GSE87420 | GEO

The effect of CDK6 expression on the murine transcriptome

Project description:We performed RNA-seq analyses in BCR-ABL+ cells either expressing or lacking CDK6. 3 replicates per group were analysed.

2020-11-24 | GSE145219 | GEO

The effect of CDK6 expression on DNA methylation and DNMT3B regulation

Project description:We performed methylation analyses in BCR-ABL+ cells either expressing or lacking CDK6 using the next-generation sequencing approach RRBS and identified DNA methylation changes towards both hyper- and hypomethylation. CDK6 mediated methylation changes are largely reverted by CDK6 re-expression in this experimental system.

2020-11-24 | GSE145218 | GEO

Mus musculus

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

| PRJNA137685 | ENA

Procyanidin-induced apoptosis of esophageal adenocarcinoma cells is mediated via stress-activated protein kinase activation of JUN-dependent transcription.

Project description:Epidemiologic studies have shown a significant inverse correlation between fruit and vegetable consumption and incidence of esophageal adenocarcinoma. Procyanidins are polymeric flavanols found in many fruits and vegetables, and have been shown to possess anti-carcinogenic/chemopreventive properties. We previously showed that an oligomeric procyanidin extracted from apples with an average degree of polymerisation of 3.9 induced cell cycle arrest and apoptosis in the esophageal adenocarcinoma cell line OE33. In order to understand the mechanism of action of this procyanidin we determined genome-wide transcriptomic changes induced by procyanidin treatment of OE33 cells. Pathway analysis of these data implicated the MAP kinase signalling pathways in eliciting these responses. An investigation into the role of these pathways showed that procyanidin specifically induced the activation of the stress-activated protein (SAP) kinases JNK1/2 and p38-? and M-^V? leading to the increased expression of JUN and the phosphatases DUSP1 and -10. Gene-specific knockdown of the expression of JNK1, JNK2, p38-?, p38-? or JUN diminished procyanidin-induced effects on apoptosis demonstrating a clear role for these pathways. JUN is a component of the transcription factor AP-1 and AP-1 binding sites are over-represented in the promoters of procyanidin-induced genes, which together with the demonstration that JUN occupies several such promoters highlight the importance of this transcription factor in mediating the cellular response to procyanidin. These data provide a mechanistic understanding of how procyanidin specifically targets distinct pathways involved in the induction of apoptosis in esophageal adenocarcinoma cells and will inform future studies investigating its use as a chemopreventive/therapeutic agent.

2011-06-16 | E-MEXP-2993 | biostudies-arrayexpress

Gene profiling of v-Src transformed primary chicken embryo fibroblasts (CEFs) under the condition of AP-1 repression

Project description:To investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEF expressing either the c-Jun dominant-negative mutant TAM67 or JunD shRNA.

2016-10-10 | GSE69862 | 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

| PRJNA659666 | ENA

STAP-1 is Required for Maintenance of Leukemic Stem Cells in Chronic Myeloid Leukemia.

Project description:The family of signal transduction adapter proteins (STAPs) has been reported to be involved in a variety of intracellular signaling and transcriptional molecules. We originally cloned STAP-2 as a c-fms interacting protein and found the effects on chronic myeloid leukemia (CML) leukemogenesis. STAP-2 binds to BCR-ABL, up-regulates BCR-ABL phosphorylation and activates its downstream molecules. In this study, we evaluated the role of STAP-1, another member of the family, in CML pathogenesis. The expression of human STAP-1 is aberrantly upregulated in CML stem cells (LSCs) in patient bone marrow. Using experimental model mice, we revealed that deletion of STAP-1 prolonged survival of CML mice with the induced apoptosis of LSCs. The impaired phosphorylated status of STAT5 by STAP-1 ablation results in downregulation of anti-apoptotic genes, BCL-2 and BCL-xL. Interestingly, transcriptome analyses indicate that STAP-1 affects several signaling pathways related to BCR-ABL, JAK2 as well as PPARγ. This adaptor protein directly binds not only BCR-ABL, also STAT5 proteins, showing synergistic effects of STAP-1 inhibition on the treatment with BCR-ABL or JAK2 tyrosine kinase inhibitor. It is known that the inhibition of BCR-ABL alone cannot eliminate CML LSCs. Our results have identified STAP-1 as a regulator of CML LSCs and support the evidence as a novel therapeutic target for CML cure.

2020-07-15 | GSE127984 | GEO

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