In the Mark Dawson laboratory, researchers aim to understand the role of epigenetic regulators in normal and malignant haemopoiesis.
They aim to use these insights to identify novel therapies for the treatment of blood cancers by: identifying epigenetic regulators important for the initiation, maintenance and progression of haematological tumours; studying epigenetic control of self-renewal in blood stem cells and cell fate decisions in normal haemopoiesis; pre-clinical characterisation of novel epigenetic therapeutic agents; and translation of our discoveries in the laboratory into early-phase clinical trials.
Epigenetic therapies we have helped develop
BET inhibitors are an exciting and novel class of epigenetic therapy that disrupts the ability of epigenetic reader proteins, such as BRD4, to recognise and bind specific histone modifications on the nucleosome. We have been integral to the development of these novel agents as cancer therapies. Based on promising pre-clinical data, these exciting new cancer drugs have entered early-phase clinical trials for patients with haematological cancers. We have recently started studying mechanisms of therapeutic resistance, to identify strategies that will improve the clinical efficacy of these drugs.
Identifying epigenetic regulators important for the initiation, maintenance and progression of haematological tumours
The genomic era has highlighted the critical role that aberrant epigenetic regulation plays in the pathogenesis of many haematological malignancies. Central to this issue is the perturbation of chemical modifications of histones and DNA, so-called epigenetic modifications (top image). The information conveyed by these modifications is essential in directing all DNA-based processes, such as transcription, DNA repair and replication. Consequently, when these epigenetic enzymes or readers are mutated, they may culminate in the induction and/or maintenance of various cancers.
Our laboratory uses a variety of model systems of haemopoietic cancers, both in vitro and in vivo, to study the role of epigenetic regulators in the initiation and maintenance of these diseases. We have employed cutting edge genetic technologies, including shRNA and CRISPR/Cas9, to identify novel genetic dependencies that can be subjected to therapeutic manipulation. These insights are used to develop targeted therapies alongside our collaborators in academia and industry. These small molecules are then validated in our pre-clinical models of haematological malignancies and ultimately transitioned into the clinical arena (bottom image).
Studying epigenetic control of self-renewal and cell fate decisions in normal haemopoiesis
Haemopoiesis is a highly orchestrated and dynamic process that not only sustains the homeostatic needs of the organism, but is also able to urgently respond to a myriad of stressors. Integral to the successful coordination of this process are decisions relating to self-renewal, lineage commitment and differentiation. Underlying these key cell fate decisions are dynamic and rapid alterations in transcription programs, which are in turn directed by essential and highly conserved epigenetic regulators. Epigenetic proteins invariably act as part of multisubunit macromolecular complexes that survey the epigenetic landscape, bind to specific chromatin modifications and act to further modify and remodel chromatin, leading to changes in gene expression. Using a range of cutting edge genetic, biochemical, bioinformatic, cell and molecular biology techniques, coupled to sophisticated in vitro and in vivo modelling, we are aiming to uncover the key epigenetic regulators that direct self-renewal and lineage commitment in haemopoiesis.
Studying genetic and epigenetic tumour heterogeneity
The advent of global sequencing technologies has highlighted that every cancer displays marked heterogeneity in DNA mutations and gene expression programs. This intra-tumour heterogeneity underpins the unpredictable natural history of all malignancies. It is also the primary driver for the variable response often observed to conventional and targeted chemotherapies. Little is known about how clonal heterogeneity at the level of the genome, transcriptome and epigenome influences the initiation and maintenance of blood cancers, and how this clonal heterogeneity is altered by conventional and targeted therapies.
Deciphering this complexity at the single cell level holds the key to a more comprehensive understanding of the biology of cancer. Furthermore, understanding the adaptive responses to therapies holds the promise of improving therapeutic outcomes. Using innovative single-cell genomic tools, we are endeavouring to address these issues.
Tyler DS, Vappiani J, Cañeque T, Lam EYN, Ward A, Gilan O, Chan YC, Hienzsch A, Rutkowska A, Werner T, Wagner AJ, Lugo D, Gregory R, Ramirez Molina C, Garton N, Wellaway CR, Jackson S, MacPherson L, Figueiredo M, Stolzenburg S, Bell CC, House C, Dawson SJ, Hawkins ED, Drewes G, Prinjha RK, Rodriguez R, Grandi P, Dawson MA (2017). Click chemistry enables preclinical evaluation of targeted epigenetic therapies. Science.356(6345):1397-1401. doi: 10.1126/science.aal2066. Epub 2017 Jun 30. Abstract | Reprint | Full text
Dawson MA (2017). The cancer epigenome: Concepts, challenges, and therapeutic opportunities. Science.355(6330): 1147-1152. DOI: 10.1126/science.aam7304. Epub 2017 Mar 17. Reprint
Gilan O, Lam EYN, Becher I, Lugo D, Cannizzaro E, Joberty G, Ward A, Wiese M, Fong CY, Ftouni S, Tyler D, Stanley K, MacPherson L, Weng CF, Chan YC, Ghisi M, Smil D, Carpenter C, Brown P, Garton N, Blewitt ME, Bannister AJ, Kouzarides T, Huntly BJP, Johnstone RW, Drewes G, Dawson SJ, Arrowsmith CH, Grandi P, Prinjha RK and Dawson MA (2016). Functional interdependency of BRD4 and DOT1L in MLL leukemia. Nat Struct Mol Biol.23(7):673-81.
Fong CY, Gilan O, Lam EYN, Rubin AF, Ftouni S, Tyler D, Stanley K, Sinha D, Yeh P, Morison J, Giotopoulos G, Lugo D, Jeffrey P, Lee SCW, Carpenter C, Gregory R, Ramsay RG, Lane SW, Omar Abdel-Wahab, Kouzarides T, Johnstone R, Dawson SJ, Huntly BJP, Prinjha RK, Papenfuss AT and Dawson MA (2015). BET inhibitor resistance emerges from leukaemia stem cells. Nature.525(7570):538-542.
Dawson MA and Kouzarides T (2012). Cancer epigenetics: from mechanism to therapy. Cell.150(1):12-27.
Dawson MA, Kouzarides T and Huntly BJP (2012). Targeting epigenetic readers in cancer. N Engl J Med.367(7):647-57.
Dawson MA*, Prinjha RK, Dittman A, Giotopoulos G, Bantscheff M, Chan W-I, Robson SC, Chung C-W, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJP* and Kouzarides T* (2011). Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature.478(7370): 529-33 (*Equal corresponding author)
Dawson MA, Bannister AJ, Göttgens B, Bartke T, Foster SD, Green AR and Kouzarides T (2009). JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin. Nature.461(7265):819-22.