Abstract 5810: Fyn kinase negatively regulates telomere length in stem cells and cancer cells

Abstract

Abstract Telomere maintenance is on the critical biological process in stem cell, aging, and cancer. Cells maintain telomere either by Telomerase (TERT) dependent pathway or by alternative lengthening of telomere (ALT) pathway. Here we report a link between Fyn kinase expression and telomere length. Fyn deficient mouse and mouse embryonic stem cells (mESC) maintain a stable telomere length through activation of ALT pathway. Fyn deficient mice are also resistant to the aging process as compared to wild type mice. We uncover a novel molecular mechanism of telomere maintenance. Menin, an essential component of an MLL/SET1 histone methyltransferase (HMT) complex that specifically methylates 'Lys-4' of histone H3 (H3K4), is a potential phosphorylation target of Fyn. Phosphorylation of Menin facilitates SUMOylation and binding to Telomerase RNA Component (TERC). The telomere dysfunction is one pivotal reason for many genetic disorders, including telomere related diseases like dyskeratosis congenita (DC). Currently, there are no curative therapies for these diseases of telomere dysfunction. We knockout Fyn gene from DC mice model and also used 4-Amino-5-(4-chlorophenyl)-7-(dimethyl ethyl) pyrazolo[3,4-d]pyrimidine (PP2), a selective inhibitor of Fyn kinase. Our results demonstrate that Fyn could be a therapeutic target in telomere related diseases. Knockout of Fyn or inhibition of Fyn by using inhibitor improves DC phenotype in mice like bone marrow failure. Human iPSC generated from DC patient's skin fibroblast shows higher expression of p-Menin and maintains a stable telomere length when we inhibited Fyn. Citation Format: Souren Paul, Thi My Le Le, Joohyun Ryu, Ki Beom Bae, Ann M. Bode, Zigang Dong. Fyn kinase negatively regulates telomere length in stem cells and cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5810.