Rewiring the interplay between GATA1s and secondary mutations in the leukaemogenic transformation

Acquired mutations in exon 2 of GATA1 -in the background of trisomy 21- produce an N-terminus truncated protein, named GATA1s driving transient abnormal myelopoiesis (TAM) in newborns with Down syndrome. Additional mutations however are required to transform the pre-leukaemic TAM clones into a full-blown acute leukaemia (ML-DS). Prior work revealed common secondary mutations in ML-DS patients belonging to epigenetic modifiers, signalling pathways and cohesin complex, which were shown causative for leukaemic transformation in a murine model. However, with the observed mutational repertoire open questions remained. Here, we are utilising virus-free CRISPR techniques to introduce GATA1s and additional mutations in primary human foetal haematopoietic stem and progenitor cells. Xenotransplantation assays of edited cells showed a marked production of immature CD117 + CD41+ megakaryocytic progenitors. Comprehensive in vitro and in vivo functional assays will provide insight into the genetic players of TAM and ML-DS oncogenesis.

Publikationsverlauf

Artikel online veröffentlicht:
13. Mai 2020