There is growing evidence that altered expression, function or localisation of epigenetic enzymes can play a crucial role in cancer onset and progression. The enzymatic activities of chromatin modifiers play important roles in tightly regulating gene expression through the remodeling of chromatin and these enzymes are promising targets for therapeutic interventions intended to reverse aberrant epigenetic states associated with cancer.
Acute myeloid leukemia (AML) is a malignant disorder of progenitor cells in myeloid hemopoiesis. AML is driven by co-operating genetic lesions typically involving Ras signaling pathways and chromosomal translocations. Our aim was to analyse AML that results from the t(8;21) chromosomal translocation that gives rise to the AML1-ETO fusion protein, or through translocations of the MLL gene at chromosome 11q23 that result in oncogenic fusion proteins that include the N-terminal region of MLL. In particular we study AML driven by the MLL-ENL [t(11;19)(q23;p13.3)] and MLL-AF9 [t(9;11)(p22;q23)] fusion proteins as these represent the majority of MLL-rearranged AML, and patients harboring these mutant proteins typically respond poorly to standard chemotherapies. A common feature of AML1-ETO, MLL-ENL and MLL-AF9 is that these proteins all aberrantly recruit epigenetic regulatory proteins including histone deacetylases (HDACs), and/or histone methytransferases (HMTs) and/or transcription elongation factors such as pTEFb. We hypothesise that dysregulated epigenetic activity underpins the onset and progression of AML driven by oncogenic fusion proteins such as AML1-ETO and MLL-ENL MLL-AF9. Therefore targeting the epigenetic enzymes that drive this process, or other proteins important for the transcriptional-regulatory function of these proteins will result in therapeutic benefit. We have used state-of-the-art genetically engineered mouse models of cancer to identify the proteins and pathways necessary for AML growth and/or survival using parallel genetic and pharmacologic approaches. Our pre-clinical studies have identified novel effective and safe therapeutic strategies for the treatment of these haematological malignancies and functional studies have identified the key molecular and biological processes that underpin the therapeutic responses.