Romidepsin in combination with niacinamide is effective therapy in a genetically engineered mouse model (GEMM) of spontaneous aggressive B-cell lymphoma expressing Bcl6. GEMM of a C57BL with λ-MYC overexpressed crossed with a mCherry fluorescent luminescent CD19 was used to assess effectiveness and tolerability of romidepsin in combination with niacinamide in the context of a normal immune system and microenvironment. (A) Whole-cell lysates prepared from the mediastinum and spleen of an untreated λ-MYC overexpressing mouse expresses similar quantities of Bcl6 and p53 as the GC-derived DLBCL cell line, OCI-Ly1, as compared with ABC-derived DLBCL cell line, Su-DHL2. (B) GEMM λ-MYC overexpressing mouse treated with niacinamide (40 mg/kg) and romidepsin (2.3 mg/kg) intraperitoneally and euthanized 5 hours later. Lysates prepared from the lymphoid tissue of the treated mouse and a control mouse were evaluated for acetylated-Bcl6 by immunoprecipitation, and Blimp1, acetylated-p53, total p53, and p21 by Western blot analysis. (C) Treatment schedules for groups of animals receiving both niacinamide and romidepsin. Schedules varied only by the sequence of the 2 drugs, with mice treated according to schedule N + R receiving romidepsin on day 1, and those treated according to schedule N→R receiving romidepsin on day 3. (D) Bioluminescence signal intensity of CD19 luminescence in representative mice from each cohort on day 1 prior to treatment, and day 22, 1 week following completion of treatment. (E) Mice were injected with 150 mg/kg d-luciferin and anesthetized after 5 minutes with a mixture of 2% isofluorane/air. Bioluminescence of each mouse was acquired by IVIS system (Xenogen) and analyzed with Living Image software (Xenogen) as a function of time for each cohort. (F) Summary of the toxicity and response to therapy at day 22 from the start of treatment. (G) Estimated rate of growth of each cohort of mice. The change of log intensity in the N + R cohort is significantly slower than the control cohort (P ≤ .01).