Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies

Yasuhiro Kazuki, Yuwna Yakura, Satoshi Abe, Mitsuhiko Osaki, Naoyo Kajitani, Kanako Kazuki, Shoko Takehara, Kazuhisa Honma, Hirofumi Suemori, Satoshi Yamazaki, Tetsushi Sakuma, Tsutomu Toki, Ritsuko Shimizu, Hiromitsu Nakauchi, Takashi Yamamoto, Mitsuo Oshimura

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13 Citations (Scopus)

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.

Original languageEnglish
Article number6136
JournalScientific reports
Volume4
DOIs
Publication statusPublished - 2014 Aug 27

ASJC Scopus subject areas

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    Kazuki, Y., Yakura, Y., Abe, S., Osaki, M., Kajitani, N., Kazuki, K., Takehara, S., Honma, K., Suemori, H., Yamazaki, S., Sakuma, T., Toki, T., Shimizu, R., Nakauchi, H., Yamamoto, T., & Oshimura, M. (2014). Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies. Scientific reports, 4, [6136]. https://doi.org/10.1038/srep06136