Figure 4. I-BET151 is efficacious in in vivo murine models and primary patients samples of MLL-fusion leukaemia.
(A) Murine pharmacokinetic studies (mean ± SD (n = 4 per compound)) comparing the blood concentration of I-BET151 with I-BET762 and JQ1. (B) Kaplan-Meier curve of control and treated NOD-SCID mice transplanted with 1 × 107 MV4;11 cells. Green arrowhead = treatment commencement D21. (C) Haematoxylin and eosin (H&E) stained histological sections of the renal parenchyma of control and treated mice. Black arrows highlight leukaemic infiltration. (D) Representative FACS analysis from the peripheral blood of control or I-BET151 treated mice. (E) Kaplan-Meier curve of control and treated C57BL/6 mice transplanted with 2.5 × 106 syngeneic MLL-AF9 leukaemic cells. Green arrowhead = treatment commencement D9. (F) Photomicrograph of the spleen size from 5/8 control and 1/12 I-BET151 treated mice that died on day 12. (G) H&E stained histological sections of the liver parenchyma from control and IBET151 treated mice demonstrating reduced disease burden in the treated animal. (H) Peripheral blood white cell count, (I) liver weight and (J) spleen weights from all the control and treated mice at the time of necropsy. (K) Representative FACS analysis assessing apoptosis from a patient with MLL-AF6 leukaemia. (L) Clonogenic assays with human MLL-fusion LSC isolated by FACS sorting (CD34+/CD38-) and plated in the presence of DMSO or I-BET151. (M) Gene-expression changes in human MLL-fusion leukaemia cells following treatment with I-BET151 or DMSO. The log2 fold change in the expression level for all genes (expression level with IBET151 treatment/expression level with DMSO) is represented. (N) Schematic model proposing the mode of action for I-BET151 in MLL-fusion leukaemia.