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DOI: 10.1055/s-0039-1687141
Identification of GATA1 s interaction partners in Down syndrome-associated myeloid leukemia
Publication History
Publication Date:
20 May 2019 (online)
Children with Down syndrome (DS) are at high risk of developing myeloid leukemia (ML-DS). Up to 30% of newborns with DS develop a pre-leukemic transient abnormal myelopoiesis (TAM). TAM is characterized by GATA1 mutations (GATA1 s) that result in a shorter form lacking the N-terminal transactivation domain. How trisomy 21 cooperates with GATA1 s in TAM development is not fully understood. In a CRISPR/Cas9 screen, RUNX1 lost resulted in depletion of ML-DS cells. Additionally, we observed differential RUNX1 isoform expression in AMKL (non-DS) and ML-DS primary cells compared to normal hematopoietic stem/progenitor cells or terminally differentiated cells. In a newly established TAM/ML-DS assay, GATA1 s synergized with particular isoforms leading to a hyperproliferative phenotype in vitro and induction of leukemia 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 analyzing all isoforms of a gene when studying its function in leukemogenesis.