Elucidating the role of CHD4 as a chromatin and epigenetic modifier in acute myeloid leukaemia

Phenotype analysis of CHD4-/- models showed DNA damage marker 53BP1 increases significantly, highlighting the increased DNA damage response which was accompanied by reduced cellular proliferation in CHD4-/- cells. Cell cycle analysis showed a decrease in cells entering the S and G2/M phases alongside an increase in cells in G1 phase suggesting a potential cell cycle checkpoint deficiency causing stunted proliferation. We measured the response of CHD4-/- cells in response to chemotherapy drugs commonly used in AML.

A drug screen (160 DNA damaging compounds) showed an increased sensitivity of CHD4-/- cells to compounds targeting DNA/RNA synthesis and the topoisomerase pathways, indicating that CHD4 is furthering the damage caused by improper cell cycle leading to cell death. Our data has identified a role of CHD4 in AML progression mediated through loss of cell cycle progression control and an elevated DNA damage response. Therefore, targeting cells with lower CHD4 expression with compounds affecting cellular differentiation/ proliferation may have an impact on patient outcome.<br><br><i>Thesis is embargoed until 31 July 2027</i>.<br><br>