BCOR LOSS IMPACTS SHH MEDULLOBLASTOMA FORMATION VIA TRANSCRIPTIONAL UP-REGULATION OF IGF2
Neuro-oncology(2018)
Abstract
Sonic hedgehog (SHH) medulloblastoma (MBSHH) accounts for approximately 25% of all MB diagnoses and is the predominant disease subgroup in infants and adults. In addition to obligatory constitutive activation of SHH signaling, previous studies have indicated the requirement of secondary genetic hits for transformation of cerebellar granule cell progenitors (GNPs) to MBSHH. Recent MB genomic studies have identified subgroup-specific recurrent mutations of chromatin modifiers. However, functional evidence substantiating a role for these mutations in MBSHH progression is currently lacking. Here, we report the first evidence that BCOR, a subunit of the PRC1.1 complex targeted by deleterious mutations in ~10% of MBSHH patients, functions as an inhibitor of MBSHH progression. Given that BCOR mutants in human MBSHH commonly lack the PUFD domain, we utilized Bcor-knockout mice that recapitulate loss of this functional domain. Conditional genetic ablation of Bcor in GNPs strongly accelerated tumor formation in Ptch1+/- mice. Transcriptional analyses revealed ~100-fold upregulation of Igf2 in Bcor-deficient Ptch1+/- MBs versus controls. Igf2 upregulation was only observed in neoplastic lesions but not in developing granule cells, indicating potential epigenetic regulation of Igf2 during tumorigenesis. Forced expression of Igf2 in Ptch1+/- GNPs generated tumors with 100% penetrance. In human MBSHH, we observed a striking association between deleterious BCOR mutations and high IGF2 expression, substantiating the results observed in transgenic mice. Thus, Bcor attenuates Igf2 expression in transforming GNPs, loss of which cooperates with aberrant SHH signaling to promote Igf2-dependent tumor growth. Ongoing work involves studying the molecular mechanisms underlying Bcor-dependent Igf2 regulation.
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Key words
up-regulation
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