Identification of common and distinct epigenetic reprogramming properties of core-binding factor fusion proteins

Loke, Justin Ching Ting (2017). Identification of common and distinct epigenetic reprogramming properties of core-binding factor fusion proteins. University of Birmingham. Ph.D.

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Abstract

RUNX1, also known as CBFa, is a master regulator of haematopoiesis. In Acute Myeloid Leukaemia (AML) it is frequently disrupted by translocations to different epigenetic regulators, resulting in the expression of core-binding factor fusion proteins.
We compared the chromatin landscape of t(8;21) and t(3;21) AML which express RUNX1-ETO and RUNX1-EVI1,
respectively. We found that the diverse clinical outcomes of patients with these two forms of AML are reflected in fundamental differences in gene expression and chromatin landscape. Despite both fusion proteins sharing a RUNT DNA binding domain, we show that RUNX1-EVI-1 targets a more immature stem cell-related gene expression program of genes as compared to RUNX1-ETO.
Despite the differences in the epigenomic landscape of t(3;21) and t(8;21) leukaemia, knockdown of either core-binding factor fusion protein activates a common myeloid differentiation program involving up regulation of C/EBPa. By blocking C/EBPa DNA binding through a dominant negative partner, we showed that this factor is required for the downstream effects of RUNX1-EVI-1 knockdown.
Even in the continued presence of RUNX1-EVI-1, ectopic expression of C/EBPa. is sufficient to initiate myeloid differentiation in t(3;21) cells. Overall, this suggests that deregulation of C/EBPa is a common pathway in the development of both t(8;21) and t(3;21) AML.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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