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The HBP1 tumor suppressor is a druggable ALK downregulated gene controlling MYCN activity

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Abstract
ALK is an important druggable target in ALK mutant neuroblastoma (NB). In this study, we sought novel vulnerable nodes downstream of ALK for combinatorial therapy. First, we identified a 79-gene signature that recapitulates the transcriptional response upon ALK inhibition based on transcriptome profiling of ALK wild type, ALKF1174L or ALKR1275Q mutant and ALK amplified NB cell lines following ALK inhibition using NVP-TAE684, LDK-378, X-396 and Crizotinib. This signature was validated in primary tumor samples and in the SK-N-AS cell line with regulated expression of ALK wild type, ALKF1174L and ALKR1275Q constructs. The majority of the mutant ALK dependent downstream signaling components were implicated in MAPK/ERK, PI3K/AKT/mTOR, MYC/MYCN and neuronal differentiation signaling. Bioinformatic analysis using the iRegulon Cytoscape plugin (http://iregulon.aertslab.org) resulted in the identification of the transcriptional repressor HBP1 as a hub gene, acting downstream of ALK. HPB1 is a known negative regulator of MYC/MYCN activity. Using MYCN and miR-17-92 inducible SHEP model systems, we established a MYCN/miR-17-92/HBP1 positive feedback regulatory loop in which MYCN represses the negative control of HBP1 through upregulation of miR-17-92 which targets the HBP1 3'UTR. Next, we showed that stable HBP1 overexpression inhibits growth and induces apoptosis of NB cells. Finally, we explored the effects of the green tea compound epigallocatechin gallate (EGCG) on HBP1 upregulation in NB cells. EGCG treatment induced HBP1 expression and had a strong negative effect on cell growth and survival. EGCG/ALK inhibitor combination treatment in a panel of cell lines showed clear additive effects. In conclusion, we identified HBP1 as a novel important ALK downregulated gene controlling MYCN activity, further stressing the important interconnection between oncogenic MYCN and ALK signaling. EGCG upregulates HBP1 levels and is a strong candidate for further in vivo testing for additive or synergistic effects with ALK inhibitors or MYCN targeting compounds such as JQ1.

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MLA
Claeys, Shana, Candy Kumps, Irina Lambertz, et al. “The HBP1 Tumor Suppressor Is a Druggable ALK Downregulated Gene Controlling MYCN Activity.” ANR Cologne 2014 : Information Book. Cologne, Germany: Uniklinik Köln, 2014. 114–115. Print.
APA
Claeys, Shana, Kumps, C., Lambertz, I., De Brouwer, S., Lindner, S., Van Goethem, A., Van Maerken, T., et al. (2014). The HBP1 tumor suppressor is a druggable ALK downregulated gene controlling MYCN activity. ANR Cologne 2014 : information book (pp. 114–115). Presented at the Advances in Neuroblastoma Research 2014 (ANR 2014), Cologne, Germany: Uniklinik Köln.
Chicago author-date
Claeys, Shana, Candy Kumps, Irina Lambertz, Sara De Brouwer, Sven Lindner, Alan Van Goethem, Tom Van Maerken, et al. 2014. “The HBP1 Tumor Suppressor Is a Druggable ALK Downregulated Gene Controlling MYCN Activity.” In ANR Cologne 2014 : Information Book, 114–115. Cologne, Germany: Uniklinik Köln.
Chicago author-date (all authors)
Claeys, Shana, Candy Kumps, Irina Lambertz, Sara De Brouwer, Sven Lindner, Alan Van Goethem, Tom Van Maerken, Jorge Vialard, Jan Cools, Johannes Schulte, Katleen De Preter, and Franki Speleman. 2014. “The HBP1 Tumor Suppressor Is a Druggable ALK Downregulated Gene Controlling MYCN Activity.” In ANR Cologne 2014 : Information Book, 114–115. Cologne, Germany: Uniklinik Köln.
Vancouver
1.
Claeys S, Kumps C, Lambertz I, De Brouwer S, Lindner S, Van Goethem A, et al. The HBP1 tumor suppressor is a druggable ALK downregulated gene controlling MYCN activity. ANR Cologne 2014 : information book. Cologne, Germany: Uniklinik Köln; 2014. p. 114–5.
IEEE
[1]
S. Claeys et al., “The HBP1 tumor suppressor is a druggable ALK downregulated gene controlling MYCN activity,” in ANR Cologne 2014 : information book, Cologne, Germany, 2014, pp. 114–115.
@inproceedings{4430922,
  abstract     = {ALK is an important druggable target in ALK mutant neuroblastoma (NB). In this study, we sought novel vulnerable nodes downstream of ALK for combinatorial therapy. First, we identified a 79-gene signature that recapitulates the transcriptional response upon ALK inhibition based on transcriptome profiling of ALK wild type, ALKF1174L or ALKR1275Q mutant and ALK amplified NB cell lines following ALK inhibition using NVP-TAE684, LDK-378, X-396 and Crizotinib. This signature was validated in primary tumor samples and in the SK-N-AS cell line with regulated expression of ALK wild type, ALKF1174L and ALKR1275Q constructs. The majority of the mutant ALK dependent downstream signaling components were implicated in MAPK/ERK, PI3K/AKT/mTOR, MYC/MYCN and neuronal differentiation signaling. Bioinformatic analysis using the iRegulon Cytoscape plugin (http://iregulon.aertslab.org) resulted in the identification of the transcriptional repressor HBP1 as a hub gene, acting downstream of ALK. HPB1 is a known negative regulator of MYC/MYCN activity. Using MYCN and miR-17-92 inducible SHEP model systems, we established a MYCN/miR-17-92/HBP1 positive feedback regulatory loop in which MYCN represses the negative control of HBP1 through upregulation of miR-17-92 which targets the HBP1 3'UTR. Next, we showed that stable HBP1 overexpression inhibits growth and induces apoptosis of NB cells. Finally, we explored the effects of the green tea compound epigallocatechin gallate (EGCG) on HBP1 upregulation in NB cells. EGCG treatment induced HBP1 expression and had a strong negative effect on cell growth and survival. EGCG/ALK inhibitor combination treatment in a panel of cell lines showed clear additive effects.
In conclusion, we identified HBP1 as a novel important ALK downregulated gene controlling MYCN activity, further stressing the important interconnection between oncogenic MYCN and ALK signaling. EGCG upregulates HBP1 levels and is a strong candidate for further in vivo testing for additive or synergistic effects with ALK inhibitors or MYCN targeting compounds such as JQ1.},
  author       = {Claeys, Shana and Kumps, Candy and Lambertz, Irina and De Brouwer, Sara and Lindner, Sven and Van Goethem, Alan and Van Maerken, Tom and Vialard, Jorge and Cools, Jan and Schulte, Johannes and De Preter, Katleen and Speleman, Franki},
  booktitle    = {ANR Cologne 2014 : information book},
  language     = {eng},
  location     = {Cologne, Germany},
  pages        = {114--115},
  publisher    = {Uniklinik Köln},
  title        = {The HBP1 tumor suppressor is a druggable ALK downregulated gene controlling MYCN activity},
  year         = {2014},
}