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Gene expression changes induced by Evi1 withdrawal in Evi1 dependent myeloid clone C6

ABSTRACT: The transcription factor Evi1 is essential for the formation and maintenance of hematopoietic stem cells, and induces clonal dominance with malignant progression upon constitutive activation by chromosomal rearrangements or transgene integration events. To understand the immediate and adaptive response of primary murine hematopoietic cells to the transcriptional upregulation of Evi1, we developed an inducible lentiviral vector system with a robust expression switch. We found that Evi1 delays differentiation and promotes survival in myeloid culture conditions, orchestrating a battery of genes involved in stemness (Aldh1a1, Ly6a [Sca1], Abca1, Epcam, among others). Importantly, Evi1 suppresses Cyclins and Cyclin-dependent kinases (Cdk), while it upregulates Cdk inhibitors, inducing quiescence in various proliferation-inducing cytokine conditions and operating in a strictly dose-dependent manner. Hematopoietic cells with persisting Evi1-induction tend to adopt a relatively low expression level. We thus classify Evi1 as a dormancy-inducing oncogene, likely requiring epigenetic and genetic compensation for cell expansion and malignant progression. Evi1 dependent myeloid clone C6 cells expressing a Doxycyclin inducible codon-optimized murine Evi1 were harvested at day 2 after DOX withdrawal and compared to C6 cells under Doxycyclin 1 ug/ml

ORGANISM(S): Mus musculus

SUBMITTER: Adrian Schwarzer

PROVIDER: E-GEOD-34755 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression changes induced by overexpression of EVI1 in Lin- hematopoietic cells [EVI1_ST]

Project description:The transcription factor Evi1 is essential for the formation and maintenance of hematopoietic stem cells, and induces clonal dominance with malignant progression upon constitutive activation by chromosomal rearrangements or transgene integration events. To understand the immediate and adaptive response of primary murine hematopoietic cells to the transcriptional upregulation of Evi1, we developed an inducible lentiviral vector system with a robust expression switch. We found that Evi1 delays differentiation and promotes survival in myeloid culture conditions, orchestrating a battery of genes involved in stemness (Aldh1a1, Ly6a [Sca1], Abca1, Epcam, among others). Importantly, Evi1 suppresses Cyclins and Cyclin-dependent kinases (Cdk), while it upregulates Cdk inhibitors, inducing quiescence in various proliferation-inducing cytokine conditions and operating in a strictly dose-dependent manner. Hematopoietic cells with persisting Evi1-induction tend to adopt a relatively low expression level. We thus classify Evi1 as a dormancy-inducing oncogene, likely requiring epigenetic and genetic compensation for cell expansion and malignant progression. Lin- Rosa26rtTA cells were isolated, transduced either with pRRL.PPT.Tet.Evi1.IRES.EGFP.pre or with the pRRL.PPT.Tet.EGFP.pre control vector in S3F11 cytokines, induced the next day with DOX [1 μg/ml] and 20 hours later sorted for EGFP expressing cells, from which total RNA was extraced and subjected to Microarray Analysis.

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