MYST Histone AcetylTransferases as Therapeutic Targets in Acute Myeloid Leukaemia

Closing date: 25/03/2024

MB-PhD Project: MYST Histone AcetylTransferases as Therapeutic Targets in Acute Myeloid Leukaemia

Lead Supervisors: Prof. Georges Lacaud
Co-Supervisors:
Prof. Tim Somervaille, Dr Daniel Wiseman, Dr Sam Butterworth

Applications Deadline: Monday 25 March 2024

Project Keywords: AML, Epigenetic, Therapies
Research Opportunity: Intercalated PhD, leading to the award of PhD and MBChB

The project supervisor is offering a PhD in the below area during 2024/2025. Work during the Summer Placement might involve some of this work but could vary.

Project Outline

Cytotoxic therapy has been the standard of care over the last 30 years for Acute Myeloid Leukaemias (AMLs). Unfortunately, more often than not, it fails to cure patients, and the 5 years survival rate is only around 20%. Therefore, there is a pressing need for the development of more specific and efficient therapies. To this end, the Stem Cell Biology laboratory investigates the mechanisms driving initiation and maintenance of leukaemia. Our overarching goals are to improve patient outcomes by identifying and validating therapeutic targets for leukaemia treatment. 

We, like others, have recently identified the histone acetyltransferases (HAT) of the MYST family as genetic dependencies in AML, and in particular some of the most aggressive AML, MLL-related AMLs (MLL-r). However, MLLr AMLs represent a spectrum of translocation and clinical disease. In this proposal, we will first define the subtypes of MLLr AML dependent on these HATs which may benefit from targeted therapy using shRNA, CRISPR, inhibitors and PROTACs strategies to target these HATs. We will also explore the potential benefits of targeting these HATs in other AMLs, notably, NPM1 mutated AMLs that have strong molecular similarities with MLLr. We will then explore at the molecular level through single-cell RNA-seq and ChIP-seq approaches how targeting these HATs disrupts the expression of crucial genes for AML maintenance and facilitates cell apoptosis or differentiation. Finally, we evaluate the effectiveness of combining HAT-targeting strategies with established or novel drugs both in vitro and in animal models. 

These comprehensive studies will employ in vitro biochemical and cellular assays, in vivo mouse models, and gene transcription and chromatin assays, providing extensive training in cellular and molecular haematopoiesis, oncology, state-of-the-art single cell technologies, and mouse modelling. 

About Prof. Georges Lacaud (project Lead Supervisor)

Georges graduated as a biotechnology engineer from the European Biotechnology School of Strasbourg (ESBS) in Strasbourg, France. He obtained his PhD from the University Louis Pasteur of Strasbourg, France and then did a postdoctoral fellowship at the National Jewish Medical Center in Denver, Colorado, USA studying early lymphoid cell development in Prof. Gordon Keller’s lab. Georges next moved to the Mount Sinai School of Medicine in New York, NY, USA where he worked on early hematopoietic development.

In 2003, he joined the CRUK Manchester Institute as a junior group leader. He is a senior group leader and heads the Stem Cell Biology group. Georges was awarded a Professorship in Stem Cell Biology at The University of Manchester in 2018.

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Headshot of Prof. Georges Lacaud,

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