Abstract
Children with Down syndrome (DS) are susceptible to two blood disorders, transient abnormal myelopoiesis (TAM) and Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL). Mutations in GATA binding protein 1 (GATA1) have been identified as the cause of these diseases, and the expression levels of the resulting protein, short-form GATA1 (GATA1s), are known to correlate with the severity of TAM. On the other hand, despite the presence of GATA1 mutations in almost all cases of DS-AMKL, the incidence of DS-AMKL in TAM patients is inversely correlated with the expression of GATA1s. This discovery has required the need to clarify the role of GATA1s in generating the cells of origin linked to the risk of both diseases. Focusing on this point, we examined the characteristics of GATA1 mutant trisomy-21 pluripotent stem cells transfected with a doxycycline (Dox)-inducible GATA1s expression cassette in a stepwise hematopoietic differentiation protocol. We found that higher GATA1s expression significantly reduced commitment into the megakaryocytic lineage at the early hematopoietic progenitor cell (HPC) stage, but once committed, the effect was reversed in progenitor cells and acted to maintain the progenitors. These differentiation stage-dependent reversal effects were in contrast to the results of myeloid lineage, where GATA1s simply sustained and increased the number of immature myeloid cells. These results suggest that although GATA1 mutant cells cause the increase in myeloid and megakaryocytic progenitors regardless of the intensity of GATA1s expression, the pathways vary with the expression level. This study provides experimental support for the paradoxical clinical features of GATA1 mutations in the two diseases.
Highlights
Children with Down syndrome (DS) are known to be susceptible to two blood disorders in their early years
In order to precisely analyze the effect of GATA-binding protein 1 (GATA1) genotype on the hematopoietic differentiation process, we prepared two sets of isogenic PSC pairs with trisomy of chromosome 21
Because the predominant restoration of erythroid differentiation was observed at this time (S10C–S10E and S11C–S11E Figs), these results indicated that GATA1fl at the endogenous expression level is important for the commitment to both erythroid and megakaryocytic lineages, but a higher expression at this stage leads to a significant bias towards erythroid commitment due to its essential role in erythropoiesis, which suppresses megakaryocyte commitment
Summary
Children with Down syndrome (DS) are known to be susceptible to two blood disorders in their early years. Various mutations in exons 2 to 3 of GATA1 result in the loss of the full-length protein (GATA1fl) and the production of only the short-form protein (GATA1s) translated from the second ATG site, which lacks the amino-terminal activation domain [10, 28]. This means that, regardless of the pattern of the mutation, the resulting protein is always a single alternative form produced even without the mutation, albeit in small amounts.
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