BET and CDK Inhibition Reveal Differences in the Proliferation Control of Sympathetic Ganglion Neuroblasts and Adrenal Chromaffin Cells

SIMPLE SUMMARY: Neuroblastoma is a childhood tumor of the sympathetic nervous system. Abdominal tumors that arise in the adrenal differ genetically and clinically from tumors that develop from sympathetic ganglia. Adrenal chromaffin cells and ganglionic neuroblasts are derived from different lineages, raising the possibility that their diverse tumor characteristics are due to different tumor founder cells. To identify traits that are specific to the candidate founder cells of adrenal and ganglionic tumors, cultures of mouse chromaffin cells and sympathetic neuroblasts were treated with a panel of proliferation inhibitors that affect various signaling pathways. Transcription-related inhibitors (BET, CDK7/12/13) showed differential effects, indicating that the BET protein and CDK signaling pathways differ in their relevance for proliferating chromaffin cells and sympathetic neuroblasts. Thus, the oncogenic aberrations affecting these pathways should differ in their efficiency and result in selective propagation, which may lead to adrenal and ganglionic tumors having different characteristics. ABSTRACT: Neuroblastoma arising from the adrenal differ from ganglionic neuroblastoma both genetically and clinically, with adrenal tumors being associated with a more severe prognosis. The different tumor properties may be linked to specific tumor founder cells in adrenal and sympathetic ganglia. To address this question, we first set up cultures of mouse sympathetic neuroblasts and adrenal chromaffin cells. These cultures were then treated with various proliferation inhibitors to identify lineage-specific responses. We show that neuroblast and chromaffin cell proliferation was affected by WNT, ALK, IGF1, and PRC2/EZH2 signaling inhibitors to a similar extent. However, differential effects were observed in response to bromodomain and extraterminal (BET) protein inhibitors (JQ1, GSK1324726A) and to the CDK-7 inhibitor THZ1, with BET inhibitors preferentially affecting chromaffin cells, and THZ1 preferentially affecting neuroblasts. The differential dependence of chromaffin cells and neuroblasts on BET and CDK signaling may indicate different mechanisms during tumor initiation in sympathetic ganglia and adrenal.