6533b82efe1ef96bd129322c
RESEARCH PRODUCT
11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
Joachim T. SiawWei-yun LaiAna P. BerbegallPer KognerTommy MartinssonGunhild TrøenGunhild TrøenMalin ÖStenssonAngela Martinez-monleonRose-marie SjöbergJimmy Van Den EyndenDan E. LindRuth H. PalmerHelena CarénAnna DjosKlaus BeiskeKlaus BeiskeNiloufar JavanmardiRosa NogueraSusanne FranssonBengt Hallbergsubject
0301 basic medicineTranscription GeneticCarcinogenesisChromaffin CellsRetinoic acidlaw.inventionNeuroblastomachemistry.chemical_compound0302 clinical medicinelawNerve Growth FactorMedicine and Health Sciencesretinoic acidAnaplastic Lymphoma Kinaselcsh:QH301-705.5NeuronsMice Inbred BALB CNeural crestCell DifferentiationPrognosisCandidate Tumor Suppressor GeneDLG2Up-RegulationCell biologyGene Expression Regulation NeoplasticERKPhenotypeTreatment Outcomemedicine.anatomical_structureFemaleChromosome Deletiontumor suppressorMAP Kinase Signaling SystemSp1 Transcription FactorSchwann cellGenetics and Molecular BiologyTretinoinBiologyGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciencesAdrenergic AgentsCell Line TumorNeuroblastomamedicineAnimalsHumansProgenitor cellGenePsychological repressionCell ProliferationChromosomes Human Pair 11Tumor Suppressor Proteinsmedicine.disease030104 developmental biologyALKlcsh:Biology (General)chemistryTrk receptorGeneral BiochemistrySuppressorSchwann CellsGuanylate Kinases030217 neurology & neurosurgerydescription
High-risk 11q deleted neuroblastomas typically display undifferentiated/poorly differentiated morphology. Neuroblastoma is thought to develop from Schwann cell precursors and undifferentiated neural crest (NC) derived cells. It is therefore vital to understand mechanisms involved in the block of differentiation. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in maintenance of undifferentiated NC-derived progenitors via repression of DLG2, a tumor suppressor in neuroblastoma. DLG2 is expressed in the ‘bridge signature’ that represents the transcriptional transition state when neural crest cells or Schwann Cell Precursors become chromaffin cells of the adrenal gland. We show that restoration of DLG2 expression spontaneously drives neuroblastoma differentiation highlighting the importance of DLG2 in this process. Further, genetic analysis of high-risk 11q-deletion neuroblastomas identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other ‘bridge genes’ may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastoma.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-09-01 | SSRN Electronic Journal |