Gene editing or autophagic delivery of mutant Mpl to the cell surface rescue receptor function in vitro. Gene editing or autophagic delivery of mutant.

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Gene editing or autophagic delivery of mutant Mpl to the cell surface rescue receptor function in vitro. Gene editing or autophagic delivery of mutant Mpl to the cell surface rescue receptor function in vitro. (A) Transient overexpression of GRASP55 tagged with a V5 epitope results in accumulation of the lower-molecular-weight core-glycosylated form of Mpl regardless of WT or mutant status. Receptors are shown to be signaling competent on the basis of phosphorylation of key signaling proteins in the Jak/STAT and PI3K pathways in response to Tpo. (B-C) XTT-II proliferation assays performed on UT-7 or Ba/F3 cell lines expressing WT or mutant MplmNG and selected for growth in the presence of Tpo (panel C, solid lines) or eltrombopag (Elt) (panel C, dotted lines). CRISPR-Cas9–edited cells that were reverse-engineered to restore the WT sequences in MPL exon 5 from the mutated W272R sequence (labeled Mpl W272R>WT) are represented by blue open circles. UT-7 cells were edited by using the D10A Cas9 mutant and 2 single gRNAs in a double nickase approach. A classical WT Cas9 approach (ie, coupled to a unique single gRNA) was used to edit Ba/F3 cells. **P < .005; ***P < .0001. Cédric Cleyrat et al. Blood Adv 2017;1:1815-1826 © 2017 by The American Society of Hematology