Identifying gene targets for drug repurposing to preventing myeloid malignancies

Preventing myeloid malignancies in children with cancer predisposition syndromes is a major obstacle. A third of neonates with DS exclusively express GATA1s – the short isoform of hematopoietic transcription factor GATA1 – causing transient abnormal myelopoiesis (TAM). TAM can clonally evolve to ML-DS. With the aim to design strategies that prevent the progression from preleukemia to overt leukemia in children with Down syndrome, we performed CRISPR-Cas9 loss-of-function and differentiation screens of FDA approved drug targets in cell lines and pre-leukemic blasts. Early stages of the ML-DS fetal genetic landscape were modeled by inducing the pathognomonic GATA1 mutations in fetal cells using the CRISPR-Cas9 system alongside known chromosome 21 oncogenes. Next-generation sequencing revealing 30 promising potential drug targets, promoting differentiation and/or impairing proliferation, which were individually validated. The success of this approach is combining fast forward genetic approaches with targeting a yet-undiscovered therapeutic window, leading to the identification of medically important and already approved drugs.

Publication History

Article published online:
17 May 2022