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The ALK downregulated target gene HBP1 and repressor of MYCN activity as synergistic target for combined PI3K/HDAC inhibition [RNA-Seq]

ABSTRACT: ALK mutations occur in 10% of primary neuroblastoma and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype with very poor prognosis. To anticipate to future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor, will be essential to understand treatment responses and failure as well as to ensure improved design of drugging combinations. We show that mutant ALK downregulates the HMG-box transcription factor 1 (HBP1) through the PI3K-AKT-FOXO3a signaling axis. Interestingly, we also demonstrate that HBP1 is under control of MYCN, through negative regulation of the miR-17~92 cluster. Moreover, modulation of HBP1 in neuroblastoma negatively affect MYCN activity, including alleviating MYCN/PRC2 controlled gene repression. Combined targeting of PI3K and MYCN signaling induced strong synergistic blocking of tumor growth, thus offering potential for targeted therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95189 | GEO | 2019/02/14

REPOSITORIES: GEO

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The ALK downregulated target gene HBP1 and repressor of MYCN activity as synergistic target for combined PI3K/HDAC inhibition [microarray]

Project description:ALK mutations occur in 10% of primary neuroblastoma and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype with very poor prognosis. To anticipate to future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor, will be essential to understand treatment responses and failure as well as to ensure improved design of drugging combinations. We show that mutant ALK downregulates the HMG-box transcription factor 1 (HBP1) through the PI3K-AKT-FOXO3a signaling axis. Interestingly, we also demonstrate that HBP1 is under control of MYCN, through negative regulation of the miR-17~92 cluster. Moreover, modulation of HBP1 in neuroblastoma negatively affect MYCN activity, including alleviating MYCN/PRC2 controlled gene repression. Combined targeting of PI3K and MYCN signaling induced strong synergistic blocking of tumor growth, thus offering potential for targeted therapeutic interventions.

2019-02-14 | GSE94811 | GEO

The ALK downregulated target gene HBP1 and repressor of MYCN activity as synergistic target for combined PI3K/HDAC inhibition

Project description:The ALK downregulated target gene HBP1 and repressor of MYCN activity as synergistic target for combined PI3K/HDAC inhibition

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Expression data from neuroblastoma of TH-MYCN/KI Alk mice

Project description:Neuroblastoma is an embryonal neoplasm that remains of dramatic prognosis in its aggressive forms. Activating mutations of the ALK tyrosine kinase receptor have been identified in sporadic and familial cases of this cancer. We generated knock-in mice carrying the two most frequent Alk mutations observed in neuroblastoma patients. We used microarrays to detail the global programme of gene expression underlying the impact of ALK mutations on neuroblastoma formation in a MYCN amplified background. We selected several murine neuroblastoma tumors for RNA extraction and hybridization on Affymetrix microarrays. We generated three groups of tumors: 10 MYCN amplified tumors, 11 MYCN amplified/ALK F1174L tumors and 10 MYCN amplified/ALK R1275Q tumors.

2014-06-24 | E-GEOD-46583 | biostudies-arrayexpress

ALK upregulates POSTN and WNT signaling to drive neuroblastoma

Project description:The goal of this study is to identify the mechanism for how ALK promotes tumorigenesis in neuroblastoma. We developed a human stem cell model of neuroblastoma and generated isogenic tumors using MYCN and MYCN/ALK. RNAseq analysis of both tumors revealed an enrichment in focal adhesion signaling and allowed us to find POSTN as a key mediator of ALK-mediated tumor growth.

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Transcriptional profiles of transgenic ALK^F1174L/MYCN vs. MYCN tumors

Project description:The ALK^F1174L mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALK^F1174L in the neural crest. Comapred to mice expressing ALK^F1174L or MYCN alone, combined expression of the two aberrations led to development of neuroblastoma with a shorter latency and higher penetrance. Here, we evaluated the transcriptional profiles of MYCN-driven neuroblastomas with or without the expression of ALK^F1174L to determine the pathogenic consequences of the ALK^F1174L/MYCN interaction in neuroblastoma. 10 mice were analysed in this study. Five ALK^F1174L/MYCN tumors were compared with five MYCN tumors. Total RNA was extracted, samples were labeled and processed using the Agilent Low Input Quick Amp two color Cy3(sample) and Cy5 (mouse reference) labeling kit and hybridized to Agilent SurePrint G3 Mouse Gene Expression arrays.

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Transcriptional profiles of transgenic ALK^F1174L/MYCN vs. MYCN tumors

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HBP1 inhibits the development of type 2 diabetes mellitus through transcriptional activation of the IGFBP1 gene

Project description:Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that is highly prevalent worldwide and characterized by glucose and lipid metabolism disorders. However, the pathogenic mechanisms have not been fully established. Here, we found that HMG-box transcription factor 1 (HBP1) is involved in T2DM and that its deficiency in mice aggravates the features of diabetes. In addition, we undertook screening by RNA sequencing and found that HBP1 activates the transcription of the insulin-like growth factor binding protein 1 (IGFBP1) gene. Moreover, Insulin and palmitic acid reduced HBP1 protein expression and inhibited its binding to the IGFBP1 promoter. Furthermore, HBP1 reduced the serum free insulin-like growth factor 1 (IGF-1) concentration through IGFBP1 and inhibited the PI3K/AKT signaling pathway. This forms an insulin/HBP1/IGFBP1 negative feedback regulatory loop to dynamically regulate blood glucose and insulin concentrations. These findings have elucidated a mechanism whereby HBP1 and its negative feedback regulatory loop influence the development of T2DM, thereby providing a new theoretical basis and potential therapeutic target for T2DM.

2022-09-26 | GSE214089 | GEO

Expression profiling of murine neuroblastoma in transgenic mice

Project description:Neuroblastoma is an embryonal tumor arising from the neural crest. It can be mimicked in mice by neural crest-specific overepxression of oncogenes such as MYCN or mutated ALK. Expression profiling of murine neuroblastoma driven by MYCN were compared to those driven by mutated ALK and to mouse normal adrenal tissue.

2012-03-31 | E-GEOD-32386 | biostudies-arrayexpress

Expression data from neuroblastoma of TH-MYCN/KI RetM919T mice

Project description:The RET gene has been identified previously as a target of activated ALK at the mRNA level in both human neuroblastoma cell lines and primary tumors as well as in murine tumors driven by mutated Alk and MYCN. Moreover, it has been shown that tumor growth of murine TH-MYCN/KI Alkmut tumors was impaired upon Ret inhibition by the vandetanib inhibitor, suggesting RET as a therapeutic target in ALK mutated neuroblastoma. To further demonstrate the crucial role of RET in ALK mutated driven neuroblastoma oncogenesis, transgenic TH-MYCN mice were bred with KI RetM919T tumors. We document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We used microarrays to analyze the global programme of gene expression of MYCN/RetM919T tumors and compare these profiles with profiles of MYCN/Alkmut tumors (GSE46583). Altogether, our data show that MYCN/RetM919T tumors present with expression profiles close to MYCN/Alkmut tumors.

2017-09-15 | GSE72678 | GEO

RNA-seq of TH-MYCN driven neuroblastoma mice +/- ALK F1178S mutation and +/- ALKAL2 overexpression

Project description:ALK is a tyrosine kinase receptor and oncogene in neuroblastoma (NB). The receptor is activated by the ALKAL2 ligand, but it is unknown whether missregulation of this ligand may play a role in NB carcinogenesis. Here, a TH-MYCN driven neuroblastoma mice was created +/- ALK F1178S mutation and +/- ALKAL2 overexpression

2020-11-24 | E-MTAB-9600 | biostudies-arrayexpress

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