Abstract
Infants with Down syndrome (DS) are at a high risk of developing transient abnormal myelopoiesis (TAM). A GATA1 mutation leading to the production of N-terminally truncated GATA1 (GATA1s) in early megakaryocyte/erythroid progenitors is linked to the onset of TAM and cooperated with the effect of trisomy 21 (Ts21). To gain insights into the underlying mechanisms of the progression to TAM in DS patients, we generated human pluripotent stem cells harbouring Ts21 and/or GATA1s by combining microcell-mediated chromosome transfer and genome editing technologies. In vitro haematopoietic differentiation assays showed that the GATA1s mutation blocked erythropoiesis irrespective of an extra chromosome 21, while Ts21 and the GATA1s mutation independently perturbed megakaryopoiesis and the combination of Ts21 and the GATA1s mutation synergistically contributed to an aberrant accumulation of skewed megakaryocytes. Thus, the DS model cells generated by these two technologies are useful in assessing how GATA1s mutation is involved in the onset of TAM in patients with DS.
Highlights
Infants with Down syndrome (DS) are at a high risk of developing transient abnormal myelopoiesis (TAM)
A GATA1 isoform (GATA1s) mutation leading to the production of N-terminally truncated GATA1 (GATA1s) in early megakaryocyte/erythroid progenitors is linked to the onset of TAM and cooperated with the effect of trisomy 21 (Ts21)
It has been reported that DS-TAM is most likely caused by a combination of the single GATA1 mutation and constitutive Ts21, and DS-related acute megakaryoblastic leukaemia (DS-AMKL) evolved from a TAM clone that acquired additional mutation(s)[9]
Summary
To gain insights into the underlying mechanisms of the progression to TAM in DS patients, we generated human pluripotent stem cells harbouring Ts21 and/or GATA1s by combining microcell-mediated chromosome transfer and genome editing technologies. The DS model cells generated by these two technologies are useful in assessing how GATA1s mutation is involved in the onset of TAM in patients with DS. Down syndrome (DS), or trisomy 21 (Ts21), is the most frequent live-born aneuploidy syndrome in humans[1], and new-born infants with DS are at a high risk of developing transient abnormal myelopoiesis (TAM)[2]. In vitro studies using DS-ES and DS-iPS cells reproduced the haematopoietic abnormalities in DS15–17, DS-derived pluripotent stem cells with an acquired GATA1 mutation have not been generated. We generated novel Ts21, GATA1s, and GATA1s/Ts21 human ES cells by combining chromosome transfer and genome editing technologies
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