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. 2017 Sep 18;114(40):E8448–E8457. doi: 10.1073/pnas.1711449114

Fig. 1.

Fig. 1.

Construction, survival, and histology of KitV558Δ/+, KitV558Δ;Y567F/Y567F, and KitV558Δ;Y719F/Y719F knock-in mice. (A) Schematic representation of targeted amino acids in the KIT protein. V558∆, oncogenic mutation due to deletion of valine 558; V558∆;T669I, double mutant containing the V558∆ and imatinib-resistant T669I mutations; V558∆;Y567F, double mutant containing the V558∆ and Y567F mutations; V558∆;Y719F, double mutant containing the V558∆ and Y719F mutations. Y567F, the docking site for the SFK tyrosine 567, is replaced by phenylalanine; Y719F, the docking site for the PI3K tyrosine 719, is replaced by phenylalanine. (B) Kaplan–Meier survival plot showing increased survival of KitV558Δ;Y567F/Y567F mice compared with fully signaling-competent KitV558Δ/+ mice. Survival of KitV558Δ;Y719F/Y719F mice was indistinguishable from that of WT mice (P = 0.791). Survival of KitV558Δ;Y567F/Y567F mice was significantly different from that of KitV558Δ;Y719F/Y719F and WT mice (P = 0.0003 and 0.0004, respectively). All survival curve comparisons are based on the log-rank/Mantel–Cox method. Median survival: KitV558Δ/+, 3 mo; KitV558Δ;T669I/+, 14 mo; KitV558Δ;Y567F/Y567F, 21 mo; KitV558Δ;Y719F/Y719F, 28 mo; WT, 29 mo. Values for KitV558Δ/+, KitV558Δ;T669I/+, and WT mice are from ref. 11. n ≥ 43 each; ticks indicate censored subjects. (C) Representative H&E-stained sections of FFPE samples of stomach, cecum, and colon from 3-mo-old mice. Arrows in a–c and j–l indicate the plane of normal myenteric plexus ICCs between the circular and longitudinal smooth muscle layers in WT and KitV558Δ;Y719F/Y719F mice. Bars in d, f, g, and i show hyperplastic extensions of this plane in gastric/colonic sections of KitV558Δ/+ and KitV558Δ;Y567F/Y567F mice. The tumor lesions in the cecum of KitV558Δ/+ (e) and KitV558Δ;Y567F/Y567F (h) mice exhibit typical GIST morphology with spindle-shaped/epithelioid tumor cells. The histology of KitV558Δ;Y719F/Y719F mice resembles that of WT mice. (Scale bar: 100 µm.) (Magnification, 10× in a, 20× in b–l). n ≥3 animals each.