Foxo1 knockout vAbl transformed cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Kwan Chow
PROVIDER: E-GEOD-46031 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2013-04-07 | E-GEOD-45837 | biostudies-arrayexpress
Project description:Foxo1 is required for proper developmental progression due to distinct functions at different stages of B cell development, but specific gene targets in pro-B cells are not identified. We performed a microarray analysis in v-Abl transformed pro-B cells to compare the gene expression pattern between wildtype and Foxo1 knockout cells.
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Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
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Project description:VEGF induces elongation of endothelial cells (ECs) that are derived from wild-type (Foxo1(+/+)) ES cells. VEGF-induced EC elongation is an important process of angiogenesis. ECs derived from Foxo1(-/-) ES cells fail to elongate in response to VEGF. Gene expression profiling of wild-type and Foxo1(-/-) ECs in the presence or absence of VEGF stimulation identifies responsible genes that regulate EC elongation. One wild-type (Foxo1(+/+)) ES cell clone and one Foxo1(-/-) ES cell clone were used. ES cells were cultured on OP9 stromal cell layer in the presence or absence of VEGF (10 ng/ml). After 6.5 days, VE-cadherin+ CD31+ ECs were isolated by FACS and used for total RNA extraction. Three independent experiments were performed for each condition.
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Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
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