CK1δ/ε inhibitor PF-670462 delays leukemic onset in the Eµ-TCL1 transgenic mouse model of CLL. (A) Typical disease development in the model used in panels B through G. (B) Scheme of experiment. (C) Delay in the leukemia onset in the case of CK1 inhibitor treated group is presented as a difference in WBC counts. Only mice in the control group (N = 16) significantly progressed between months 6 and 7 (P = .0036, paired Student t test); CK1 inhibitor treated mice: N = 13, paired Student t test. The WBC counts were significantly different between groups after the treatment period (P = .0030, unpaired Student t test). Results from 2 independent experiments were merged together. WBC (normalized value): 0% = the lowest value in each data set; 100% = the highest value in each data set. Columns represent median. (D) Repeated treatment by the CK1 inhibitor at months 6 to 7 and 10 to 11 significantly delays progression of the disease, measured as a ratio of mice with highly progressed stage/dead mice vs mice with early stage of the disease in time (P = .0142, χ2 test). Dead of leukemia refers to mice that had enlarged spleen and had detectable progressed leukemia at the last PB sampling before death. (E) The inhibitor-treated mice lived significantly longer compared with the control group (N = 13 treated vs 16 control animals, experiments 1 and 2 merged; P = .0257, log-rank test). Overall survival is presented starting from the sixth month = start of the first treatment cycle. (F) Organ sizes were analyzed at the end of the experiment or at the time of death. WT, age-matched nontransgenic wild-type C57BL/6 littermates. (Fi) Spleens of the inhibitor treated mice were significantly smaller compared with the control group (N = 12 treated, 13 control and 3 WT animals, P = .0114, Mann-Whitney U test). (Fii) Examples of the spleens obtained by autopsy. (Fiii) A similar but not significant trend was noted in liver. Columns represent median. (G) PB analysis by hemoanalyzer was performed on 7 CK1 inhibitor treated mice and 4 control mice after the end of the survival analysis (experimental data set 1). The inhibitor treated mice were significantly less anemic, which is indicated by higher RBC counts (i) and hemoglobin (ii; HGB) or hematocrit (iii; HCT) levels compared with the control animals, close to WT littermates (N = 6). (iv) Plateletcrit (PCT) was not increased by treatment. Unpaired Student t test was used. Values are presented as mean ± SEM.
