Figure 8. Mutant EZH2 and Constitutive BCL6 Cooperate to Induce Lymphomagenesis, and Combinatorial Targeting of EZH2 and BCL6 Yields Enhanced Anti-Lymphoma Effect.

(A) Bone marrow transplantation was performed using IµBcl6, Ezh2(Y641F)^fl/WT;Cγ1-cre, Ezh2(Y641F)^fl/WT;Cγ1-cre;IµBcl6, and control negative littermate donor mice. BM, bone marrow.

(B) Survival curve of transplanted mice.

(C) Representative pictures of spleens from mice sacrificed 223 days after transplantation and quantification of the spleen weight (control, n=4; Ezh2(Y641F)^fl/WT;Cγ1-cre, n = 4; IµBcl6, n = 5; Ezh2(Y641F)^fl/WT;Cγ1-cre;IµBcl6, n = 12).

(D) Representative pictures of submandibular lymph nodes from mice sacrificed in (C).

(E) Percentage and number of mice from cohort used in (C) that did or did not develop lymphoma.

(F) Dose reduction plot for GSK343 at 90% growth inhibition after exposure of cells to increasing concentrations of GSK343 for 6 days and FX1 for 2 days. Data represent means of triplicate experiments.

(G) RT-qPCR of the indicated mRNAs from OCI-Ly7 treated with 2 µM GSK343 for 72 hr, 25 µM FX1 for 12 hr, or the combination. Values are means of triplicates ±SD.

(H and I) Tumor growth curves and area under the curve (AUC) for SUDHL6 (H) and WSU-DLCL2 (I) xenografted mice treated with vehicle (SUDHL6, n = 9; WSU-DLCL2, n = 11), GSK126 (80 mg/kg/day, SUDHL6, n = 5; WSU-DLCL2, n = 10), FX1 (12 mg/kg/day, SUDHL6, n = 4; WSU-DLCL2, n = 10), or the combination of GSK126 and FX1 (SUDHL6, n = 6; WSU-DLCL2, n = 12).

Values in (C), (H), and (I) are means ± SEM. t test, *p < 0.05, **p < 0.01, ***p < 0.001. See also Figure S8.