Fig. 5: LP-182 attenuates signal transduction and restores immune cell balance to improve cellular disease phenotypes and survival in the MPLW515L MF mouse model.
From: A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy
a Kaplan–Meier plot of MF mice treated as indicated. Data represent vehicle (n = 4), LP-182 (n = 5) animals per group. Statistical significance determined using Log-Rank (Mantel-Cox) test. b Mean fluorescence intensity values of pAKT (pS473) and pERK1/2 (pT202/pY204) in splenocytes from healthy control and MF mice treated as indicated. Data represent the mean ± s.e.m., healthy control (n = 5), vehicle (n = 4), LP-182 (n = 5) animals per group. Statistical significance determined using Two-way ANOVA corrected with Tukey’s multiple comparisons test (pAKT Healthy control vs. Vehicle, p < 0.0001; pAKT Vehicle vs. LP-182, p < 0.0001; pERK1/2 Healthy control vs. Vehicle, p < 0.0001; pERK1/2 Vehicle vs. LP-182, p < 0.0001). c Immune cell numbers from spleen of healthy control and MF mice treated as indicated. Data represent the mean ± s.e.m., healthy control (n = 5), vehicle (n = 3), LP-182 (n = 4) animals per group. Statistical significance determined using Two-way ANOVA corrected with Tukey’s multiple comparisons test (T cell Healthy control vs. Vehicle, p = 0.049; B cell Healthy control vs Vehicle, p < 0.0001; B cell Healthy control vs. LP-182, p < 0.0001; Neu Healthy control vs. Vehicle, p < 0.0001; Neu Vehicle vs. LP-182, p = 0.0002; MK Healthy control vs. Vehicle, p < 0.0001; MK Vehicle vs. LP-182, p < 0.0001). d Representative histological images and quantitation of MK cells per high-power field from spleen of MF mice treated as indicated. Hematoxylin & Eosin (H&E; 10x with 20x inset, scale 100 µm). Data represent the mean ± s.e.m., vehicle (n = 4), LP-182 (n = 5) animals per group. Statistical significance determined using two-tailed unpaired t-test (p = 0.015). e Representative immunohistochemistry images with quantitation of GFP-positive MK cells per high-power field from spleen of MF mice treated as indicated. Green Fluorescent Protein (GFP; 40x, scale 20 µm). Data represent the mean ± s.e.m., vehicle (n = 4), LP-182 (n = 4) animals per group. Statistical significance determined using two-tailed unpaired t-test (p = 0.0051). f Representative histological images with scored fibrosis grading from bone marrow of MF mice treated as indicated. Reticulin (40x, scale 20 µm). Data represent the mean ± s.e.m., vehicle (n = 4), LP-182 (n = 5) animals per group. Individual data sets and scoring details are provided in Supplementary Table 1. g Concentration of LP-182 and associated metabolites in serum and bone marrow from MF mice ~2 h following final oral administration. Data represent the mean ± s.e.m., n = 4 animals. h Immunoblot analysis and quantitation of ERK1/2 and pERK1/2 (pT202/pY204) from bone marrow of MF mice treated as indicated. Data were normalized to GAPDH and analyzed relative to ERK1/2 where indicated. Data represent the mean ± s.e.m., vehicle (n = 4), LP-182 (n = 4) animals per group. Statistical significance determined using two-tailed unpaired t-test (p = 0.0011). Source data are provided as a Source Data file. a-h MPLW515L MF mice were treated p.o. daily with vehicle (14-21 d) or LP-182 (28 d) at 400 mg kg−1.
