Decoding cellular immortality using genetically engineered human pluripotent stem cells Center for Developmental Biology

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Category	Seminar
Date and Time	2016-12-08 16:00 - 17:30
Venue	Seminar Room A7F
Speaker	Kunitoshi Chiba
Affiliation	UC-Berkeley
Title	Decoding cellular immortality using genetically engineered human pluripotent stem cells
Host	Sa-Kan Yoo
Summary	The crucial role of telomerase in stem cell maintenance and tumorigenesis has long been recognized. Telomerase deficiencies lead to accelerated telomere shortening causing bone marrow failure, aplastic anemia and pulmonary fibrosis in patients. Paradoxically, telomerase reactivation underlies the proliferative immortality of most human cancers. Telomerase is a reverse transcriptase composed of the protein TERT and the RNA template TR. The levels of telomerase activity vary depending on cell type. Stem cells are telomerase positive, while most differentiated somatic cells are telomerase negative because of the transcriptional silencing of TERT that happens during differentiation. However, in cancer cells, TERT expression is reactivated and telomeres are maintained, causing their immortal phenotype. Recently, genome-wide sequencing analysis revealed that mutations in the TERT promoter are the most frequent non-coding mutations in cancer. These mutations result in de novo E26 transformation-specific (ETS) transcription factor family binging sites and are highly prevalent, occurring in about 50% of melanoma, glioblastoma, bladder cancer, liver cancer and urothelial carcinoma cases. We used genome editing of human pluripotent stem cells (hPSCs) to elucidate the mechanisms by which these mutations contribute to human disease. hPSCs engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT expression. However, cells with TERT promoter mutations failed to silence TERT expression upon differentiation into somatic cells, resulting in residual telomerase activity and aberrantly long telomeres. These data indicate that TERT promoter mutations can confer immortalization and tumorigenesis of incipient cancer cells. Reference: Chiba et al. Elife. 2015 Jul 21;4.