Our lab has recently identified an oncogene whose epigenetic mechanism has been implicated in the development of acute myeloid leukaemia (AML). AML is considered a stem-cell disease as it can originate from a leukaemic stem cell (LSC), which possesses proliferative and self-renewal capacities. The prognosis for AML patients remains poor and LSC are considered to be the basis for disease relapse. Epigenetic therapy has the potential to be more effective and less cytotoxic over traditional therapy. Together, this suggests that LSC-targeting therapies may allow for a cure of AML with fewer adverse effects for patients. However, there are currently no therapies that directly target LSC and it is unclear which mechanistic regulators are involved in their development and maintenance.
Our microarray data identified an epigenetic regulator that is significantly overexpressed in LSC compared to normal haematopoietic stem cells (HSC), thus presenting an ideal therapeutic target. Our preliminary results showed that its overexpression not only promoted the proliferative and self-renewal capacities of pre-LSC, but also altered the epigenetic landscape. In contrast, its knock-down severely impaired the stem cell properties to the extent in which differentiation was induced. In order to explain these phenotypic changes, microarray was performed to identify downstream targets of this epigenetic regulator. In vivo studies involving secondary and tertiary transplantations have shown a significant delay in leukaemia onset and frequency. Further studies are ongoing to observe in vivo changes in leukaemic stem cell properties such as loss of proliferation and self-renewal.
In summary, our preliminary data strongly suggest that this novel epigenetic regulator is a key driver in the development of aggressive AML. Altered histone modifications indicate that this regulator disrupts the normal epigenetic landscape and activates downstream oncogenes, resulting in more aggressive AML. Targeting this abnormally expressed gene has the potential to reverse specific abnormal epigenetic marks in LSC, thereby allowing the development of epigenetic treatment strategies that will enable us to directly target and eradicate LSC.