title: Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma.
abstract: Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma.
authors.affiliation: Inserm U830, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Alex
authors.initials: A
authors.lastname: Cazes
authors.forename: Lucille
authors.initials: L
authors.lastname: Lopez-Delisle
authors.forename: Konstantina
authors.initials: K
authors.lastname: Tsarovina
authors.forename: Cécile
authors.initials: C
authors.lastname: Pierre-Eugène
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.forename: Claire
authors.initials: C
authors.lastname: Provost
authors.forename: Caroline
authors.initials: C
authors.lastname: Louis-Brennetot
authors.forename: Romain
authors.initials: R
authors.lastname: Daveau
authors.forename: Candy
authors.initials: C
authors.lastname: Kumps
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cascone
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.forename: Aurélie
authors.initials: A
authors.lastname: Prignon
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Hermann
authors.initials: H
authors.lastname: Rohrer
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
mesh_terms: D000595:Amino Acid Sequence; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015139:Blotting, Southern; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D019426:Integrases; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse; C045073:Cre recombinase; D019426:Integrases