The effect of CDK6 expression on DNA methylation and DNMT3B regulation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145218 | GEO | 2020/11/24
REPOSITORIES: GEO
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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.
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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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Project description:The cyclin-dependent kinases (CDK) CDK6 and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (HSCs and LSCs) that exceeds its function as cell-cycle regulator. Although hematopoiesis appears regular under steady state conditions Cdk6-/- HSCs do not efficiently repopulate upon competitive transplantation and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil (5-FU) treatment. We find that activation of HSCs requires CDK6, which interferes with transcription of key regulators including Egr1. The central role of Egr1 is supported by transcriptional profiling of HSCs. The impaired repopulation capacity extends to BCR-ABLp210+ leukemic stem cells. Transplantation with BCR-ABLp210+-infected bone marrow (BM) from Cdk6-/- mice fails to induce disease although recipient mice do harbor LSCs. Egr1 knock-down in cdk6-/- BCR-ABLp210+ LSKs significantly enhances colony formation underlining the importance of the Cdk6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and as essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.
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Project description:Cdk4 and Cdk6 are two related kinases that bind D-type cyclins and regulate cell cycle progression. Due to their relevance in cancer, Cdk4/6 inhibitors are currently in advanced clinical trials in multiple tumor types. Cdk4/6 are inhibited by INK4 proteins that exert tumor suppressing functions. To test the significance of this inhibitory mechanism we have generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6R/R mice display altered development of the hematopoietic system without resulting in enhanced tumor susceptibility, either in the presence or absence of p53. The presence of the Cdk6 R31C allele results in defective potential of hematopoietic progenitors in adoptive transfer assays or after induced damage. These defects are rescued after complete insensitivity to INK4 inhibitors in Cdk4R/R; Cdk6R/R double mutant mice, and INK4-resistant mice display increased susceptibility to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, the presence of the Cdk6 R31C allele results in increased binding of p16INK4a to wild-type Cdk4, whereas the double mutant is fully insensitive to INK4 inhibitors resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in tumor development and suggest a role for Cdk6 in buffering INK4 protein levels thus contributing to the development of hematopoietic tumors. The presence of the Cdk4 R24C and Cdk6 R31C alleles results in relevant changes in the expression profiles of cancer cells including deregulation of apoptosis and other processes.
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