TY - JOUR
T1 - ALK positively regulates MYCN activity through repression of HBP1 expression
AU - Claeys, Shana
AU - Denecker, Geertrui
AU - Durinck, Kaat
AU - Decaesteker, Bieke
AU - Mus, Liselot M.
AU - Loontiens, Siebe
AU - Vanhauwaert, Suzanne
AU - Althoff, Kristina
AU - Wigerup, Caroline
AU - Bexell, Daniel
AU - Dolman, Emmy
AU - Henrich, Kai Oliver
AU - Wehrmann, Lea
AU - Westerhout, Ellen M.
AU - Demoulin, Jean Baptiste
AU - Kumps, Candy
AU - Van Maerken, Tom
AU - Laureys, Genevieve
AU - Van Neste, Christophe
AU - De Wilde, Bram
AU - De Wever, Olivier
AU - Westermann, Frank
AU - Versteeg, Rogier
AU - Molenaar, Jan J.
AU - Påhlman, Sven
AU - Schulte, Johannes H.
AU - De Preter, Katleen
AU - Speleman, Frank
N1 - Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2019/4/11
Y1 - 2019/4/11
N2 - 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 3 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 3 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.
AB - 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 3 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 3 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.
UR - https://www.scopus.com/pages/publications/85058246022
U2 - 10.1038/s41388-018-0595-3
DO - 10.1038/s41388-018-0595-3
M3 - Article
C2 - 30538293
AN - SCOPUS:85058246022
SN - 0950-9232
VL - 38
SP - 2690
EP - 2705
JO - Oncogene
JF - Oncogene
IS - 15
ER -