Epigenetic programming defines stem cell identity and entry into the proliferative compartment in chronic myeloid leukaemia (CML)

QH301 Biology;RC0254 Neoplasms. Tumors. Oncology (including Cancer)

Korfi, Koorosh ; Vetrie, David

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: Epigenetic, chronic myeloid leukaemia, cancer stem cell;   

Others  :  http://theses.gla.ac.uk/3929/1/2012Korfiphd.pdf

来源: University of Glasgow

【 摘 要 】

Chronic myeloid leukaemia (CML) is a haematological malignancy that is identified by the presence of a fusion oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. The discovery of tyrosine kinase inhibitors (TKIs) over that past decade has resulted in significantly improved survival rates and disease management in CML patients. However, a subpopulation of BCR-ABL1+ cells in the niche are found which exhibit stem cell-like features, such as self-renewal and quiescence. These CML stem cells (LSCs) are shown to be insensitive to TKI treatment and are capable of deriving the disease during the relapse. Consequently, the elimination of LSCs is a primary goal of current research. Therefore, the aim of this thesis was to obtain a global view of the cellular processes that maintain stem cell identity in CD34+ CD38- LSCs as well as identify those processes which initiate the transition to proliferative CD34+ CD38+ CML progenitor cells (LPCs). A combined approach was exploited to investigate genome-wide gene expression profiles and histone modification signatures of normal HSCs and committed progenitors (HPCs), and their LSC and LPC counterparts. Despite having increased activity in pathways involved in cell division and proliferation, expression levels of the pathways involved in stem cell identity were not significantly different in LSCs to those found in HSCs. These pathways included Wnt, TGF-β signalling, and several novel neurotransmitter signalling pathways. By examining genome-wide histone modification patterns using ChIP-sequencing it was shown that the stem cell identities of HSCs and LSCs are programmed at the epigenetic level. All of the pathways which confer stem cell identity to both HSCs and LSCs are significantly enriched for bivalent gene promoters having both the H3K4me3 and H3K27me3 marks. These similarities were most evident in neurotransmitter signalling and it was demonstrated that these pathways are capable of promoting LSC maintenance in vitro. Intriguingly, although the stem cell entry into the proliferative state occurs through the repression of many of the same stem cell identity pathways in both HSCs and LSCs, it was shown that epigenetic reprogramming in CML mediates this repression via a different mechanism than in normal HSCs. Furthermore, abnormalities in levels of several chromatin enzymes were identified that are likely to be responsible for the epigenetic reprogramming of CML cells. The work presented in this thesis defines the chromatin landscape of a cancer stem cell for the first time and provides new therapeutic targets for the eradication of TKI resistant CML stem cells.