Home > Haematology > EHA 2019 > Bench-to-Bedside > Transformation of foetal haematopoietic stem and progenitor cells in the background of trisomy 21

Transformation of foetal haematopoietic stem and progenitor cells in the background of trisomy 21

Presented by
Dr Sophia Gialesaki, Hannover Medical School, Germany
Conference
EHA 2019
In the Presidential Symposium, Dr Sophia Gialesaki (Hannover Medical School, Germany) presented her functional studies aimed to understand the pathophysiology behind myeloid leukaemia predisposition in trisomy 21 [1].

Children with Down syndrome (DS) are at high risk of developing myeloid leukaemia (ML-DS). Up to 30% of DS newborns develop a pre-leukaemic transient abnormal myelopoiesis (TAM), characterised by the accumulation of immature megakaryoblasts of foetal origin. TAM is characterised by GATA1 mutations (GATA1-s) that result in a shorter protein isoform lacking the N-terminal transactivation domain. To understand how trisomy 21 cooperates with GATA1-s in TAM development, the researchers performed a CRISPR/Cas9 screen, targeting the 218 currently annotated coding genes on Hsa21 with 1,090 sgRNAs in both an ML-DS and control cell line.

RUNX1 loss resulted in depletion of ML-DS cells. Additionally, the researchers observed differential RUNX1 isoform expression in acute megakaryoblastic leukaemia (non-DS) and ML-DS primary cells compared with normal haematopoietic stem/progenitor cells or terminally differentiated cells. In a newly established TAM/ML-DS assay, GATA1-s synergised with particular isoforms leading to a hyperproliferative phenotype in vitro and induction of leukaemia in vivo. This was further confirmed by co-immunoprecipitation assays followed by mass spectrometric analysis and DNA sequencing, showing differences in the physical interactions of GATA1/GATA1-s and RUNX1 isoforms as well as at genomic loci in TAM and ML-DS. These results highlight the importance of analysing all isoforms of a gene when studying its function in leukaemogenesis, with relevance for targeted therapies.

1. Gialesaki S, et al. Abstract S146, 24th Congress of the EHA, 13-16 June 2019, Amsterdam, the Netherlands.


 



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