Pluripotent stem cell model of early hematopoiesis in Down syndrome reveals quantitative effects of short-form GATA1 protein on lineage specification

Children with Down syndrome (DS) are susceptible to two blood disorders, transient abnormal myelopoiesis (TAM) and syndrome-associated acute megakaryocytic leukemia (DS-AMKL). Mutations in GATA binding protein 1 ( GATA1 ) have been identified as the cause of these diseases, expression levels resulting protein, short-form (GATA1s), known correlate severity TAM. On other hand, despite presence mutations almost all cases DS-AMKL, incidence DS-AMKL TAM patients is inversely correlated GATA1s. This discovery has required need clarify role GATA1s generating cells origin linked risk both diseases. Focusing on this point, we examined characteristics mutant trisomy-21 pluripotent stem transfected a doxycycline (Dox)-inducible cassette stepwise hematopoietic differentiation protocol. We found that higher significantly reduced commitment into lineage at early progenitor cell (HPC) stage, but once committed, effect was reversed acted maintain progenitors. These stage-dependent reversal effects were contrast results myeloid lineage, where simply sustained increased number immature cells. suggest although increase progenitors regardless intensity expression, pathways vary level. study provides experimental support for paradoxical clinical features