Acute Myeloid Leukaemia (AML) has a dismal prognosis with less than 30% 5-year survival.
Mainstay therapy has remained essentially unchanged for the past three decades, with small advances in disease-free survival for the most part attributable to transplantation and improved supportive care.
The World Health Organization (WHO) classifies AML in seven categories based on morphology and immune phenotype criteria.
Genome sequencing studies have gone some way into defining the mutational spectrum of the disease, with identification of the most frequent recurrently mutated genes, and highlighting the presence of multiple mutations in most forms of the disease.
A significant number of the most commonly mutated targets in AML are histone modifiers, i.e. proteins or complexes that catalyse post-translational modifications in specific residues of the histone side chains.
Acetylation status of lysine residues in histone tails have been studied in some detail, and suggest evident epigenetic post-translational modifications that alter DNA-templated processes and facilitate malignant transformation.
An important acetyltransferase is KAT2A, the dominant mammalian orthologue of GCN5, in haematopoietic stem progenitor and leukaemic cells.
It has been shown that KAT2A regulates the activity of Peroxisome Proliferator Activated Receptor Gamma-Coactivator-1α, and through protein acetylation, directly regulating their transcriptional activity, key to glucose metabolism.
This proposal has had as main goal to position KAT2A as a critical regulator and therapeutic target in AML biology, crucially in the interaction with non-histone proteins and as a candidate regulator of AML metabolism.
I have performed quantitative proteomics and metabolomic analysis of Kat2a depletion in a primary mouse AML model, where we demonstrated a requirement for Kat2a in maintaining leukaemia stem cells (LSC).
I identified a defect in the usage of oxidative phosphorylation upon Kat2a loss, which did not correspond to a structural mitochondrial defect and was reversible upon cell loading with malate, a key metabolite in oxidative energy production.
Proteomics and metabolomics data can be articulated with my lab’s published datasets (where I have as well contributed ) on transcriptional and epigenetic targets of KAT2A, to define the network of events underlying KAT2A activity in AML and select potential druggable targets.
