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JDP2 - an Oncogenic bZIP Transcription Factor in T-cell Acute Lymphoblastic Leukemia

ABSTRACT: JDP2 - an Oncogenic bZIP Transcription Factor in T-cell Acute Lymphoblastic Leukemia

PROVIDER: PRJNA475108 | ENA |

REPOSITORIES: ENA

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JDP2 - an Oncogenic bZIP Transcription Factor in T-cell Acute Lymphoblastic Leukemia [ChIP-Seq]

Project description:A substantial subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) develops resistance to steroids and succumb to their disease. JDP2 encodes a bZIP protein that has been implicated as a T-ALL oncogene from insertional mutagenesis studies in mice, but its role in human T-ALL pathogenesis has remained obscure. Here we show JDP2 is aberrantly expressed in a subset of T-ALL patients and is associated with poor survival. JDP2 is required for T-ALL cell survival, as its depletion by shRNA knockdown leads to apoptosis. Mechanistically, JDP2 regulates pro-survival signaling through direct transcriptional regulation of MCL1. Furthermore, JDP2 is one of few oncogenes capable of initiating T-ALL in transgenic zebrafish. Notably, thymocytes from rag2:jdp2 transgenic zebrafish express high levels of mcl1, and demonstrate resistance to steroids in vivo. These studies establish JDP2 as a novel oncogene in high-risk T-ALL, and implicate overexpression of MCL1 as a mechanism of steroid resistance in JDP2-overexpressing cells.

2018-06-18 | GSE115465 | GEO

JDP2 - an Oncogenic bZIP Transcription Factor in T-cell Acute Lymphoblastic Leukemia [RNA-Seq]

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Project description:JDP2 - an Oncogenic bZIP Transcription Factor in T-cell Acute Lymphoblastic Leukemia [RNA-Seq]

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Project description: Not available

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JDP2 - an Oncogenic bZIP Transcription Factor in T-cell Acute Lymphoblastic Leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

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Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Project description:Dysregulation of kinase signaling pathways via mutations favors tumor cell survival and resistance to therapy and it is common in cancer. Here, we reveal a novel mechanism of post-translational regulation of kinase signaling and nuclear receptor activity via deubiquitination in acute leukemia. We observed that the ubiquitin specific protease 11 (USP11) is highly expressed in lymphoblastic leukemia and associates with poor prognosis in this disease. USP11 ablation inhibits leukemia growth in vitro and in vivo, sparing normal hematopoiesis and thymus development, suggesting that USP11 could be a therapeutic target in leukemia. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK). Deubiquitination of LCK controls its activity, thereby altering T cell receptor signaling. Impairment of LCK activity leads to increased expression of the glucocorticoid receptor transcript, culminating into transcriptional activation of pro-apoptotic target genes, and sensitizes cells to glucocorticoids in primary T cell leukemia patient samples. The transcriptional activation of pro-apoptotic target genes, such as BCL2L11, is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Pharmacological inhibition of USP7 or genetic knockout of USP7 in combination treatment of glucocorticoid displayed improved anti-T-ALL efficacy in vivo. Our data unveil how dysregulated deubiquitination controls signaling pathways, leading to cancer cell survival and drug non-response, and suggest novel therapeutic combinations towards targeting leukemia.

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