Fig. 6: MTCP1-driven murine leukemia is responsive to BTK inhibition.

A Continuous BTK inhibition via ibrutinib delays progression of a spontaneous leukemia in Eµ-MTCP1 mice most evident by 12 months of age (CD19⁺/CD5⁺, p = 0.018; CD19⁺/B220^dim, p = 0.012 determined via Cox proportional hazards model). Eµ-MTCP1 mice (n = 13 per group) began continuous dosing of ibrutinib (~30 mg/kg/day, red line) or vehicle (10% cyclodextrin, black line) via drinking water (d.w.) beginning at two months of age. Plot reflects mean ± SE. B Mice from (A) were followed, revealing continuous BTK inhibition via ibrutinib (red line) prolongs survival compared to vehicle (black line, p = 0.006). “\({\!\,}^{\ast\ast}\)” represents estimation from a Cox proportional hazards model. C Adoptive transfer of 1 × 10⁶ splenic Eµ-MTCP1 CLL-like cells via tail vein to immune competent wildtype host mice results in a progressive leukemic expansion that is delayed upon treatment with ibrutinib. Mice were enrolled to receive either ibrutinib (red line, 25 mg/kg; n = 9) or vehicle (black line, 0.5% methylcellulose/1% Tween80; n = 9) via daily (Mon-Fri) oral gavage (o.g.) upon reaching >20% CD5⁺/CD19⁺ and CD19⁺/B220^dim CD45⁺ cells in the blood. Ibrutinib administration delayed the rate of leukemic progression measured at six (p = 0.063) and 12 weeks (p < 0.001) post-engraftment. P values determined via mixed effects model. Plot reflects mean ± SE. D Median survival time for mice in (C) is significantly extended upon daily administration of oral ibrutinib (red line, median survival = 28.4 weeks), extending well beyond the median survival observed with vehicle treatment (black line, median survival = 11.4 weeks; p < 0.001). “\({\!\,}^{\ast\ast\ast}\)” represents estimation from a Cox proportional hazards model. E Post-mortem histopathology analysis of organs and tissues from mice in (C) receiving either ibrutinib (top panel) or vehicle (bottom panel) having succumbed to disease. Hematoxylin & eosin staining reveals extensive neoplastic infiltrates effacing the bone marrow and lymph nodes in both ibrutinib and vehicle treated mice, while infiltrates are less severe in the liver and spleen of mice treated with ibrutinib. Neoplastic cells are observed as discrete, basophilic nodules in the livers (arrows) and spleens (circled regions) of the ibrutinib-treated mice, whereas in the vehicle-treated mice, neoplastic cells tended to form diffuse sheets or larger/confluent nodules All organs visualized at 10x, scale bars are 200 µm.