Telomeres and telomerase are key determinants of cancer and age-associated degenerative diseases. In the previous funding period, we elucidated a telomere-p53-PGC pathway directly linking three major instigators of aging: telomere dysfunction (genotoxic stress), mitochondrial compromise and oxidative stress. Our inducible telomerase model (Tert-ER) demonstrated that restoration of telomerase activity and telomere function can reverse widespread tissue degenerative phenotypes across multiple organs, including the brain, providing a framework for the exploration of telomerase based tissue rejuvenation in the aged. In the context of cancer, the inducible Tert-ER allele enabled precise modeling of telomere-based crisis and telomerase reactivation in T cell lymphoma and prostate cancer, providing experimental proof of the role of telomere dysfunction in generating cancer-relevant genomic alterations, and of telomerase reactivation in driving cancer progression. Upon extinction of telomerase, this novel model revealed that cancer cells can re-establish telomerase- independent tumor growth via acquisition of ALT and enhance PGC-directed mitochondrial function and oxidative defense. Recent detailed analysis of telomere dysfunction in the hematopoietic system uncovered defects in gene splicing and differentiation, specifically in the common myeloid progenitor (CMP) cells, generating the first physiologically relevant model of myelodysplastic syndrome (MDS) with occasional AML transformation.
Aim 1 will elucidate how telomere dysfunction alters CMP differentiation and encourages predisposition to MDS. Employing this MDS model, high throughput Nano-ChIP-Seq will be conducted on normal vs. telomere dysfunctional CMPs to ascertain the epigenome landscapeand integrated with transcriptomic analysis to identify key epigenetic regulators and differentially spliced variants for further functional validation of their roles in disease biology This Tert-ER MDS model also affords assessment of the impact of telomerase reactivation on established MDS disease and its potential to either reverse MDS or provoke progression to AML.
Aim 2 will explore telomerase extinction as an anti-cancer therapy and define molecular responses and potential resistance mechanisms on the genomic, proteomic and metabolomic levels to anti-telomerase therapy in AML and glioma - two human cancers with prominent links to telomere biology. Similar to our work in T cell lymphoma, we will explore the tumor maintenance, cellular and molecular consequences of telomerase extinction on normal and cancer stem cells with a specific focus on the acquisition of ALT and on adaptive/resistance changes via (epi)genomic (particularly copy number, transcriptomic, epigenomic), proteomic (RPPA) and metabolomic profiling. Elucidation of these adaptive mechanisms may inform the clinical use of anti-telomerase therapy and combinations thereof in the prevention and treatment of these highly lethal cancers.
In this long-standing grant, we propose to explore the link between telomere biology, the differentiation of hematopoietic progenitor cells and myelodysplastic syndrome (MDS). We will continue to employ the inducible telomerase allele to generate a MDS model and determine the resistance mechanism(s) that emerge upon telomerase extinction in acute myeloid leukemia (AML) and glioma through functional -omic approaches.
|Boutin, Adam T; Liao, Wen-Ting; Wang, Melody et al. (2017) Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev 31:370-382|
|Ong, Derrick Sek Tong; Hu, Baoli; Ho, Yan Wing et al. (2017) PAF promotes stemness and radioresistance of glioma stem cells. Proc Natl Acad Sci U S A 114:E9086-E9095|
|Lu, Xin; Jin, Eun-Jung; Cheng, Xi et al. (2017) Opposing roles of TGF? and BMP signaling in prostate cancer development. Genes Dev 31:2337-2342|
|Zhao, Di; Lu, Xin; Wang, Guocan et al. (2017) Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542:484-488|
|Colla, Simona; Ong, Derrick Sek Tong; Ogoti, Yamini et al. (2015) Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell 27:644-57|
|Zhang, Yuqing; Shin, Sandra J; Liu, Debra et al. (2013) ZNF365 promotes stability of fragile sites and telomeres. Cancer Discov 3:798-811|
|Mourkioti, Foteini; Kustan, Jackie; Kraft, Peggy et al. (2013) Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy. Nat Cell Biol 15:895-904|
|Sahin, Ergun; DePinho, Ronald A (2012) Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol 13:397-404|
|Moslehi, Javid; DePinho, Ronald A; Sahin, Ergün (2012) Telomeres and mitochondria in the aging heart. Circ Res 110:1226-37|
|Ding, Zhihu; Wu, Chang-Jiun; Jaskelioff, Mariela et al. (2012) Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 148:896-907|
Showing the most recent 10 out of 31 publications