Targeting of aberrant epigenetic circuitries and associated DNA damage response in acute myeloid leukaemia

While advance in DNA sequencing technology has provided important insights into the genetic makeup of cancer cells, it is evident that cancers are also driven by epigenetic deregulation and tumour environments beyond the hardwired DNA mutations.

In acute myeloid leukaemia (AML), the most common initiating mutations involve transcription factors and their associated epigenetic modifiers such as retinoic acid receptor alpha, the core-binding factors (e.g., AML1 or CBF?), the mixed lineage leukaemia protein (MLL), and DNA methyltransferase 3A with clear distinctive epigenetic functions.

The importance of epigenetic deregulation in AML pathogenesis is further underscored by the discovery of 1) leukemic stem cells with identical genetic makeup but distinctive gene expression profiles and immunophenotypes as compared with their short-lived progenies; and 2) genetically indistinguishable but transcriptionally distinctive AML stem cells originates from normal haematopoietic stem cells (HSC) versus committed early myeloid progenitors (e.g., CMP, GMP) exhibited contrasting cancer biology and treatment responses.

While key epigenetic factors, polycomb group (PcG) proteins are frequently deregulated in various cancers including AML and their inhibitors have also been developed for potential cancer therapeutics, we are still in our infancy in understanding their roles and functional involvements in leukaemia development.

Intriguingly, many of their family members and associated factors also emerge as important players in governing DNA damage responses (DDR), which has been the key to the recently proposed synthetic lethality approach for AML treatment.

By applying various biochemical, molecular and cellular biology approaches in combination with sophisticated mouse disease models together with relevant patient derived leukaemia cell and xenograft models, my research programme will study the roles of epigenetic factors and DDR in AML pathogenesis with an overarching goal of developing more effective leukaemia treatments.

The programme will be divided into four major interactive sections where we will 1) investigate the roles of YY1/non-canonical polycomb repressive complex (PRC)1 and Skp/Cullin/F-box (SCF) complex in MLL-AML and other AML; 2) define the functions and downstream molecular targets of BMI1/PRC1 in malignant and normal haematopoiesis; 3) dissect the mechanisms underlying contrasting EZH2/PRC2 functions in different AML; and 4) explore the link between epigenetic regulation and DDR that may be exploited as novel cancer therapeutics.

The end product of these endeavours will be an in-depth understanding of the epigenetic regulation and transformation mechanisms underlying AML pathogenesis, which will also provide novel targets for development of better therapeutic strategies that can potentially be directly translated into patient’s benefit.