Project description

Background | Acute Erythroleukemia (AEL) is an aggressive and poor outcome subtype of AML that is largely resistant to standard treatments. Unlike other more common AML subtypes, very little is known of the genetic lesions that drive erythroid transformation, and there is a scarcity of in vivo genetic models in which to study AEL pathogenesis.

We have recently contributed to the world’s first comprehensive genome wide analysis of the genetic lesions that define AEL (Iacobucci I et al, Nature Genetics, 2019), and now have the unique opportunity to generate much needed pre-clinical models that faithfully recapitulate the genetic landscape of the human disease.

The project | Utilising novel genetic models of AEL, this project aims to study the molecular mechanisms driving transformation of the red blood cell lineage. Briefly, CRISPR/Cas9 gene editing approaches will be employed in both mouse and human cells to generate in vitro and in vivo models of AEL that faithfully recapitulate the underlying genetics identified in human AEL patients. Large scale genomic studies will be performed using these models to identify key mechanisms of erythroid transformation and AEL development. Finally, putative drug targets will be identified and tested in these model systems, with the ultimate aim of identifying novel therapeutic approaches for this very poor outcome malignancy.