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HBP1 downregulation through mutant ALK represents a novel mechanism for cooperative MYCN activation in neuroblastoma

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Abstract
Introduction: MYCN signaling plays a key role in initiation and progression of neuroblastoma (NB). Mutant ALK is implicated in accelerated MYCN-driven NB formation in mouse models. Combined MYCN-amplified/mutant ALK NBs have very poor outcome. Finally, recent data showed that ALK mutations frequently occur in relapsed tumors suggesting a specific role for ALK signaling in therapy resistance. Previous studies showed that mutant ALK activates MYCN signaling through transcriptional regulation and protein stabilization. We recently identified a third major HBP1-controlled mechanism of ALK-mediated MYCN activation. Methods: Pathway analysis of HBP1 regulation was done by in vitro analysis of transcriptional response of NB cells to compounds targeting ALK, PI3K/AKT and MAPK signaling. The SHEP cell line with inducible miR-17∼92 was used to investigate HBP1 regulation. HBP1 was modulated in the NGP cell line in order to study transcriptional networks. Data mining was performed in R using available algorithms. Results: HBP1 is regulated through PI3K/AKT-FOXO3a signaling downstream of mutant ALK and a miR-17∼92 controlled negative feedback loop, as miR-17∼92 is positively regulated by MYCN and down-regulates HBP1. EGCG (epigallocatechin gallate) was selected as a tool compound as it is known to up-regulate HBP1 (Kim et al, 2006, JBC). We demonstrate synergistic effects of combined JQ1/EGCG administration in mouse xenografts with significant growth delay in this combination-treated group. Discussion: HBP1 is an important novel NB suppressor integrated into a complex regualtory network governed by ALK and MYCN signaling and offering a novel entry point for MYCN drugging in NB.

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Chicago
Claeys, Shana, Irina Lambertz, Alan Van Goethem, Candy Kumps, Sara De Brouwer, Annelies Fieuw, Tom Van Maerken, et al. 2015. “HBP1 Downregulation Through Mutant ALK Represents a Novel Mechanism for Cooperative MYCN Activation in Neuroblastoma.” In Combined SIOPEN Annual General Meeting and 4th Neuroblastoma Research Symposium, Abstracts.
APA
Claeys, Shana, Lambertz, I., Van Goethem, A., Kumps, C., De Brouwer, S., Fieuw, A., Van Maerken, T., et al. (2015). HBP1 downregulation through mutant ALK represents a novel mechanism for cooperative MYCN activation in neuroblastoma. Combined SIOPEN annual general meeting and 4th Neuroblastoma Research symposium, Abstracts. Presented at the Combined SIOPEN annual general meeting and 4th Neuroblastoma Research symposium.
Vancouver
1.
Claeys S, Lambertz I, Van Goethem A, Kumps C, De Brouwer S, Fieuw A, et al. HBP1 downregulation through mutant ALK represents a novel mechanism for cooperative MYCN activation in neuroblastoma. Combined SIOPEN annual general meeting and 4th Neuroblastoma Research symposium, Abstracts. 2015.
MLA
Claeys, Shana, Irina Lambertz, Alan Van Goethem, et al. “HBP1 Downregulation Through Mutant ALK Represents a Novel Mechanism for Cooperative MYCN Activation in Neuroblastoma.” Combined SIOPEN Annual General Meeting and 4th Neuroblastoma Research Symposium, Abstracts. 2015. Print.
@inproceedings{7213409,
  abstract     = {Introduction: MYCN signaling plays a key role in initiation and progression of neuroblastoma (NB). Mutant ALK is implicated in accelerated MYCN-driven NB formation in mouse models. Combined MYCN-amplified/mutant ALK NBs have very poor outcome. Finally, recent data showed that ALK mutations frequently occur in relapsed tumors suggesting a specific role for ALK signaling in therapy resistance. Previous studies showed that mutant ALK activates MYCN signaling through transcriptional regulation and protein stabilization. We recently identified a third major HBP1-controlled mechanism of ALK-mediated MYCN activation. 
Methods: Pathway analysis of HBP1 regulation was done by in vitro analysis of transcriptional response of NB cells to compounds targeting ALK, PI3K/AKT and MAPK signaling. The SHEP cell line with inducible miR-17\ensuremath{\sim}92 was used to investigate HBP1 regulation. HBP1 was modulated in the NGP cell line in order to study transcriptional networks. Data mining was performed in R using available algorithms. 
Results: HBP1 is regulated through PI3K/AKT-FOXO3a signaling downstream of mutant ALK and a miR-17\ensuremath{\sim}92 controlled negative feedback loop, as miR-17\ensuremath{\sim}92 is positively regulated by MYCN and down-regulates HBP1. EGCG (epigallocatechin gallate) was selected as a tool compound as it is known to up-regulate HBP1 (Kim et al, 2006, JBC). We demonstrate synergistic effects of combined JQ1/EGCG administration in mouse xenografts with significant growth delay in this combination-treated group. 
Discussion: HBP1 is an important novel NB suppressor integrated into a complex regualtory network governed by ALK and MYCN signaling and offering a novel entry point for MYCN drugging in NB.},
  author       = {Claeys, Shana and Lambertz, Irina and Van Goethem, Alan and Kumps, Candy and De Brouwer, Sara and Fieuw, Annelies and Van Maerken, Tom and Althoff, Kristina and Schulte, Johannes and Demoulin, Jean-Baptiste and Neuroblastoma Research Consortium, the and De Preter, Katleen and Speleman, Franki},
  booktitle    = {Combined SIOPEN annual general meeting and 4th Neuroblastoma Research symposium, Abstracts},
  language     = {eng},
  location     = {Newcastle-upon-Tyne, UK},
  title        = {HBP1 downregulation through mutant ALK represents a novel mechanism for cooperative MYCN activation in neuroblastoma},
  year         = {2015},
}