Bioinformatics Seminar
Time: 11AM
Venue: Online
6 June 2023
Epigenetic alterations in pre-leukemic stem cells during T cell acute lymphoblastic leukemia development
Alex YanWEHI Bioinformatics
T-cell acute lymphoblastic leukemia (T-ALL) is a common blood malignancy in children and young adults. The genetics and transcriptome of T-ALL have been well characterized. However, how epigenetic abnormalities such as DNA hypermethylation and altered chromatin structure contribute to T-ALL pathogenesis remains to be elucidated. We used a mouse model mimicking human early T precursor ALL to investigate epigenetic changes during its initiation and evolution. We showed distinct trajectories for chromatin, DNA methylation and gene expression changes during leukemogenesis. Leukemia initiation in pre-LSC (pre-leukemic stem cells) was characterized by immature transcriptome and accessible heptad binding sites. DNA methylation heterogeneity started to accumulate in H3K27me3 and H3K4me3 bivalent regions in pre-LSC with slightly reduced chromatin accessibility and increased methylation percentage. These regions further underwent loss of H3K27me3 and DNA hypermethylation in LSC. This process repressed nearby genes which are normally lowly expressed and prevented them from re-expression. For the first time, we showed a comprehensive epigenetic landscape during T-ALL leukemogenesis, and provided new insights into the potential mechanisms driving leukemia development.