TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

Abstract

Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.

Enhancer hijacking determines intra- and extrachromosomal circular MYCN amplicon architecture in neuroblastoma

“…A large subset of neuroblastomas was recently found to be driven by a small set of transcription factors that form a self-sustaining core regulatory circuit, defined by their high expression and presence of super-enhancers [15][16][17][18] . In how far MYCN itself is directly regulated by CRC factors was previously unclear, particularly due to the challenging interpretation of epigenomic data on amplicons 16 .…”

“…Recently, studies have identified a core regulatory circuit (CRC) including half a dozen transcription factors that drive a subset of neuroblastoma with noradrenergic cell identity, including most MYCN-amplified cases [15][16][17][18] . The epigenetic landscape around MYCN is less well described.…”

A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells

“…Given that CDK7 inhibitors have been shown to suppress prooncogenic transcription by targeting enhancers in tumor cells [30][31][32][33][34][35] , we envisioned that dual inhibition of BRD4 and CDK7 might synergize to suppress the growth of BETi-resistant leukemia cells to overcome resistance. To validate this possibility, we carried out a well-established combinatorial assay on leukemia cells with increasing doses of I-BET151 (a BRD4 inhibitor) and/or THZ1 (a CDK7 inhibitor).…”

Multifocal primary neuroblastoma tumor heterogeneity in siblings with co‐occurring PHOX2B and NF1 genetic aberrations

“…Therefore, we suspect that germline PHOX2B deletion in combination with germline NF1 mutation, somatic 17q gain, or both, facilitated tumor formation as plausible “second hits” that have been previously implicated in neuroblastoma pathology. The starting point of 17q gain was not consistent among the four tumors from Patient 1, but all tumors harbored gain of the region distal to 17q21.31, which contains multiple genes that may facilitate neuroblastoma tumorigenesis or progression, including the antiapoptotic protein BIRC5/survivin, the potentially oncogenic transcription factor TBX2, and prohibitin …”