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ALK positively regulates MYCN activity through repression of HBP1 expression

Claeys, Shana; Denecker, Geertrui; Durinck, Kaat; Decaesteker, Bieke; Mus, Liselot M.; Loontiens, Siebe; Vanhauwaert, Suzanne; Althoff, Kristina; Wigerup, Caroline LU and Bexell, Daniel LU , et al. (2018) In Oncogene
Abstract

ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for 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 entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI3K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity.... (More)

ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for 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 entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI3K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI3K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.

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@article{1d27b9ca-bdd8-4170-857e-850f2eb9c0c4,
  abstract     = {<p>ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for 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 entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI<sub>3</sub>K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI<sub>3</sub>K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.</p>},
  author       = {Claeys, Shana and Denecker, Geertrui and Durinck, Kaat and Decaesteker, Bieke and Mus, Liselot M. and Loontiens, Siebe and Vanhauwaert, Suzanne and Althoff, Kristina and Wigerup, Caroline and Bexell, Daniel and Dolman, Emmy and Henrich, Kai Oliver and Wehrmann, Lea and Westerhout, Ellen M. and Demoulin, Jean Baptiste and Kumps, Candy and Van Maerken, Tom and Laureys, Genevieve and Van Neste, Christophe and De Wilde, Bram and De Wever, Olivier and Westermann, Frank and Versteeg, Rogier and Molenaar, Jan J. and Påhlman, Sven and Schulte, Johannes H. and De Preter, Katleen and Speleman, Frank},
  issn         = {0950-9232},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {ALK positively regulates MYCN activity through repression of HBP1 expression},
  url          = {http://dx.doi.org/10.1038/s41388-018-0595-3},
  year         = {2018},
}