UBC Theses and Dissertations
Epigenetic dysregulation in lymphoid leukemias Islam, Rashedul
Epigenetic modification to DNA and the histone proteins that package it maintains genome stability and helps to define the transcription program within a cell. Epigenetic programming is a dynamically regulated process essential for normal differentiation including in the blood system, a process known as hematopoiesis. Failures in normal epigenetic programming, driven by genetic mutations to, or changes in expression of, epigenetic modifiers are recurrently observed in specific blood cancers including leukemia. How epigenomic dysregulation contributes to transformation in leukemia is poorly understood and the focus of this thesis. T-cell acute lymphoblastic leukemia (T-ALL) and B-cell chronic lymphocytic leukemia (CLL) arise from the lymphoid hematopoietic lineages and are defined by the block of maturation of T- and B-cells, respectively. To characterize epigenetic dysregulation associated with T-ALL and CLL, I performed an integrative analysis spanning multiple layers of epigenomic and transcriptomic datasets generated from sorted primary leukemic blasts and cell line models. My analysis revealed a common theme of enhancer reprogramming driving an oncogenic transcription program in these leukemias. Gain-of-function mutations to NOTCH1 are amongst the most frequent genetic lesions in T-ALL. In NOTCH1 activated T-ALL cell lines, I found that Runt-related transcription factor 1 (RUNX1), a key hematopoietic transcription factor, regulates the occupancy of the active enhancer mark (H3K27ac) genome-wide. I showed that RUNX1 is required for NOTCH1 to acetylate H3K27 residues and to co-regulate the expression of known NOTCH1 target genes including MYC, NOTCH3, HES4, and DTX1. Using a bioinformatic pipeline I developed, I classified CLL patients into IGHV subtypes using RNA-seg. In the epigenomic profiles generated from primary CLL blasts classified by my pipeline, I observed that CLL has a unique landscape of enhancer marks (H3K27ac and H3K4me1) compared to normal B-cell counterparts. De novo gain of CLL-specific enhancers contributes to the generation of super-enhancers and clusters of neighboring enhancers associated with the expression of proto-oncogenes including BCL2, LEF1, FGR, and CBFA2T3. My analysis further showed differences in DNA methylation at CLL-specific enhancers classify CLL samples into two novel clinical subgroups, independent of IGHV subtype.
Item Citations and Data
Attribution-NonCommercial-NoDerivatives 4.0 International