Abstract BACKGROUND Medulloblastoma (MB), pineoblastoma (PB) and retinoblastoma (RB), three types of malignant neural pediatric brain tumors are anatomically situated in different parts of brain but share a common feature - elevated expression of a photoreceptor ‘program’. MYC-amplified MBs and PBs are often histologically indistinguishable. Both grow aggressively, often relapse after standard treatment and have a dismal prognosis. Trilateral RBs are rare but often present with aggressive eye tumors first and later on PBs. It is important to understand how these photoreceptor-positive tumors arise and to know if they could be similarly treated. CRX, a transcription factor critical for retinal and pineal cell development is also a master regulator for MB-Group3 tumor maintenance. METHODS AND RESULTS To understand if MYC-driven MB, PB and RB can arise from specific photoreceptor-positive progenitors in the developing brain, we performed Crx-lineage tracing with tamoxifen injections. We could confirm that Crx-positive cells exist in retina and in pineal gland progenitors as expected. However, Crx-traced cells also marked granule neurons in the flocculonodular lobe of the cerebellum, which is a recently suggested site of MB-Group3 origin arising from the developing rhombic lip. To investigate if the Myc oncogene can generate different types of pediatric brain tumors in Crx-positive cells from retina, pineal gland and cerebellum, XMYCT58A-Tomato and XMYC was established by crossing Crx-CreERT2 strain with a LSL-MycT58A strain and Rosa26LSL-tdTomato stain. Here stabilized Myc oncogene was turned on with tamoxifen injection after birth and red tumor cell development could be followed. XMYCT58A-Tomato mice developed brain tumors from retina, pineal gland and cerebellum after 4-6 months. Histologically, tumors were non-glial (GFAP-, Olig2-), showed neuronal activity (Neurod1+) and stained positive for photoreceptor markers (CRX+, OTX2+) similar to both MB-Group3 and PB-MYC. CONCLUSIONS Our data suggest that MYC-driven Group 3 MB, PB and RB all could originate photoreceptor positive cells, which has implications for future research and the development of novel treatments targeting these devastating childhood malignancies.
Zhao et al. (Wed,) studied this question.