SU11657 inhibits TEL-PDGFRB-induced MPD. (A) SU11657 inhibits TEL/PDGFβR autophosphorylation in animals that received a TEL-PDGFRB transplant. TEL-PDGFRB recipient mice were killed after treatment with vehicle or SU11657 for 7 days beginning 14 days after transplantation. Spleen sections of killed animals were stained for phosphorylated PDGFR by immunohistochemistry and counterstained with methyl green. (B) Splenomegaly is inhibited in TEL-PDGFRB mice treated with SU11657. Spleens of inhibitor-treated (left) and vehicle-treated (right) animals killed at day 33 after transplantation (19 days of treatment). Average spleen weight for vehicle-treated animals was 0.83 ± 0.2 g at time of death due to MPD (range, 31-61 days after transplantation; n = 5), whereas spleens of SU11657-treated animals averaged 0.04 ± 0.01 g at time of censor (33 and 94 days after transplantation after 19 and 80 days of treatment, respectively; n = 2). (C) SU11657 prolongs survival in a murine bone marrow transplantation model of TEL-PDGFRB-mediated disease. Recipient mice were treated with vehicle or inhibitor for 10 or 14 weeks, beginning 14 days after transplantation. Vehicle mice (squares) died of rapidly fatal MPD, whereas mice treated 10 weeks (triangles) and 14 weeks (diamonds) survived disease free for treatment duration. TEL-PDGFRB mice whose treatment began following the establishment of MPD and continued until 74 days after transplantation, labeled rescue (circles), also survived disease free for the duration of treatment. Censored mice, shown as open shapes, were killed to monitor disease development or GFP expression at given time points regardless of disease phenotype. Diseased animals were found dead or were killed on appearing sick (ruffled fur, weight loss, cachexia). Mice were classified with primary disease as follows: MPD (WBC count > 50 × 10⁹/L [> 50 000/μL], spleen > 45 mg; shown as filled shapes), acidophilic macrophage pneumonia (perivascular cuffing and infiltration of macrophages in the lungs, with minimal or no extramedullary hematopoiesis in liver or spleen; shown as vertical half-filled shapes), or undetermined (insufficient data; shown as horizontal half-filled shapes). ^*Three animals from the group treated on days 25 to 74 were killed at day 112 because of anemia (red blood cell count < 6 × 10¹²/L [< 6 million per μL]), but 1 of 3 mice had evidence of pneumonia by histopathologic analysis. (D) SU11657 suppresses TEL-PDGFRB-induced leukocytosis for the duration of treatment. Blood was harvested from SU11657- and vehicle-treated mice at the time points indicated and differentials were acquired from a HemaVet hematology analyzer. Median WBC counts and interquartile range are shown, with the treatment period indicated by a bar in the upper left-hand corner of the graph. Fine red horizontal line represents normal WBC count range.