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
PY - 2019/4
Y1 - 2019/4
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 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.
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 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.
KW - Anaplastic Lymphoma Kinase/genetics
KW - Animals
KW - Cell Line, Tumor
KW - Cell Proliferation/genetics
KW - Down-Regulation/genetics
KW - Forkhead Box Protein O3/genetics
KW - Gene Expression Regulation, Neoplastic/genetics
KW - High Mobility Group Proteins/genetics
KW - Humans
KW - Mice
KW - MicroRNAs/genetics
KW - Mutation/genetics
KW - N-Myc Proto-Oncogene Protein/genetics
KW - Neuroblastoma/genetics
KW - Phosphatidylinositol 3-Kinases/genetics
KW - Proto-Oncogene Proteins c-akt/genetics
KW - Repressor Proteins/genetics
KW - Signal Transduction/genetics
KW - Transcriptional Activation/genetics
U2 - 10.1038/s41388-018-0595-3
DO - 10.1038/s41388-018-0595-3
M3 - Article
C2 - 30538293
SN - 0950-9232
VL - 38
SP - 2690
EP - 2705
JO - Oncogene
JF - Oncogene
IS - 15
ER -