Rapid and reversible suppression of ALT by DAXX in osteosarcoma cells.
2019; 9 (1): 4544
Many tumors maintain chromosome-ends through a telomerase-independent, DNA-templated mechanism called alternative lengthening of telomeres (ALT). While ALT occurs in only a subset of tumors, it is strongly associated with mutations in the genes ATRX and DAXX, which encode components of an H3.3 histone chaperone complex. The role of ATRX and DAXX mutations in potentiating the mechanism of ALT remains incompletely understood. Here we characterize an osteosarcoma cell line, G292, with wild-type ATRX but a unique chromosome translocation resulting in loss of DAXX function. While ATRX and DAXX form a complex in G292, this complex fails to localize to nuclear PML bodies. We demonstrate that introduction of wild type DAXX suppresses the ALT phenotype and restores the localization of ATRX/DAXX to PML bodies. Using an inducible system, we show that ALT-associated PML bodies are disrupted rapidly following DAXX induction and that ALT is again restored following withdrawal of DAXX.
View details for DOI 10.1038/s41598-019-41058-8
View details for PubMedID 30872698
- Clonal replacement of tumor-specific T cells following PD-1 blockade. Nature Medicine 2019. 25(8):1251-9. Nature Medicine 2019; 25 (8)
Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element.
2018; 173 (6): 1398
Noncoding mutations in cancer genomes are frequentbut challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth invivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements.
View details for PubMedID 29731168
ATAC Primer Tool for targeted analysis of accessible chromatin
2018; 15 (5): 304–5
View details for PubMedID 29702633
Pembrolizumab for advanced basal cell carcinoma: an investigator-initiated, proof-of-concept study.
Journal of the American Academy of Dermatology
View details for PubMedID 30145186