Deregulation of alternative promoter usage in T-acute lymphoblastic leukemia
authors
keywords
- Promoter
- Atp2c1
- Leukemia
document type
THESEabstract
An important dimension of genome complexity is the use of alternative promoters to drive pervasive gene regulation in a cell type-specific manner and human development. Alternative promoters are frequently deregulated in disease, including cancer, thus promoter choice might be among the unknown driving forces behind the oncogenic transcriptional changes. Tcell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer resulting from the malignant transformation of T cell progenitors, to some extent due to abnormal expression of transcription factors. My thesis aimed to assess the relevance of alternative promoter deregulation in T-ALL. Integrative analysis of epigenomic and transcriptomic data in normal T-cell precursors and primary T-ALLs lead to the identification of an alternative promoter of ATP2C1 as frequently up-regulated in T-ALL patients. ATP2C1 encodes the secretory pathway Ca2+ ATPase type I pump (also known as SPCA1). The ATP2C1 pump is located on the membrane of the Golgi apparatus (GA) where it transports Ca2+ and Mn2+ ions from the cytosol into the GA, thus contributing to the secretory pathway. ATP2C1 expression has been involved in oxidative stress, cell cycle regulation, and cancer cell survival. I found that T-ALL specific promoter usage of ATP2C1 is linked to an activated T cell signaling. Analyses of gene expression and reporter assays demonstrated that the alternative ATP2C1 promoter intrinsically responds to T-cell activation. CRISPR-mediated deletion or repression of the alternative promoter resulted in the lack of activation of ATP2C1. Moreover, genetic inactivation of the ATP2C1 gene triggered exacerbated T-cell activation. I hypothesized that the epigenetic deregulation of the ATP2C1 alternative promoter might confer increased cell survival of leukemic cells by interfering with T-cell signaling.
