Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity

• Main Authors: Kenji Kubara, Kazuto Yamazaki, Yasuharu Ishihara, Takuya Naruto, Huan-Ting Lin, Ken Nishimura, Manami Ohtaka, Mahito Nakanishi, Masashi Ito, Kappei Tsukahara, Tomohiro Morio, Masatoshi Takagi, Makoto Otsu
• Format: Article
• Language: English
• Published: Elsevier 2018-08-01
• Series: Stem Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213671118302716

Summary: Oncogenic KRAS mutations in hematopoietic stem cells cause RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). KRAS plays essential roles in stemness maintenance in some types of stem cells. However, its roles in pluripotent stem cells (PSCs) are poorly understood. Here, we investigated the roles of KRAS on stemness in the context of induced PSCs (iPSCs). We used KRAS mutant (G13C/WT) and wild-type isogenic (WT/WT) iPSCs from the same RALD patients, as well as wild-type (WTed/WT) and heterozygous knockout (Δed/WT) iPSCs, both obtained by genome editing from the same G13C/WT clone. Compared with WT iPSCs, G13C/WT iPSCs displayed enforced retention of self-renewal and suppressed capacity for neuronal differentiation, while Δed/WT iPSCs showed normalized cellular characteristics similar to those of isogenic WTed/WT cells. The KRAS-ERK pathway, but not the KRAS-PI3K pathway, was shown to govern these G13C/WT-specific phenotypes, indicating the strong impact of the KRAS-ERK signaling upon self-renewal and differentiation propensity in human iPSCs. : In this article, Kubara, Yamazaki, and colleagues show that, using RALD patient-derived iPSCs, oncogenic KRAS activates mainly the MEK-ERK pathway, but not the PI3K-AKT pathway, leading to enforced retention of self-renewal and suppressed capacity for undergoing neuronal differentiation in human iPSCs. Keywords: iPSCs, KRAS, RAS-associated autoimmune lymphoproliferative syndrome-like disease, self-renewal, stemness, differentiation, MAPK pathway