Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities

• DOI: 10.1016/j.celrep.2016.04.031
• Publication Date: 2016-04-30T17:32:22Z
• Authors: Kimihiko Banno; Sayaka Omori; Katsuya Hirata; Nobutoshi Nawa; Natsuki Nakagawa; Ken Nishimura; Manami Ohtaka; Mahito Nakanishi; Tetsushi Sakuma; Takashi Yamamoto; Tsutomu Toki; Etsuro Ito; Toshiyuki Yamamoto; Chikara Kokubu; Junji Takeda; Hidetoshi Taniguchi; Hitomi Arahori; Kazuko Wada; Yasuji Kitabatake; Keiichi Ozono
• Keywords: GATA1; RUNX1; Trisomy

Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic GATA1. To better understand functional interplay between trisomy 21 GATA1 hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) genome-editing technologies. Comparative analysis engineered iPSCs demonstrated that perturbed hematopoietic development through enhanced production progenitors upregulation mutated GATA1, resulting accelerated aberrantly differentiated cells. These effects were mediated by dosage alterations RUNX1, ETS2, ERG, located a critical 4-Mb region chromosome 21. Our study provides insight into genetic synergy contributes to multi-step leukemogenesis.