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Epigenetic matrix and targeted therapy of BPDCN
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Figure 3. The efficacy of epigenetic agents in a preclinical blastic plasmacytoid dendritic cell neoplasm (BPDCN) mouse model. (A) Pharmacodynamic assessment of the percentage of human CD56+CD38+ cells in the peripheral blood (PB), bone marrow (BM) of the femur and spine, spleen, and liver of a representative vehicle- treated BPDCN mouse model, 39 days after CAL-1 injection. The cytofluorometric assays shows the tumor dissemination in all the tissues analyzed. (B) Hematoxylin & eosin (H&E) staining of BM and spleen samples collected in a representative vehicle-treated NSG mouse 39 days after CAL-1 injection (H&E; x400; Olympus DP2- SAL). The histological assay shows a marked dissemination of blast elements. The immunohistochemistry detection of the CD303 (BDCA-2) antigen, in the murine BM, indicates the presence of specific BPDCN blasts cells (Immmuno-alkaline phosphatase; Gill’s hematoxylin nuclear counterstaining; x400; Olympus DP2-SAL). These results further confirmed the effective engraftment of CAL-1 cell line. (C) Graphical representation of the treatment schedules observed in a BPDCN mouse model. Each treatment is represented by a single color or by a combination of colors and was administered for four weeks as follows: 5’-azacytidine 5 mg/kg 5 doses at 2-day intervals (green), decitabine 2.5 mg/kg 3 doses at 2-day intervals (light brown), romidepsin 0.5 mg/kg every day (violet), bortezomib 0.5 mg/kg two times weekly (fuchsia). The same doses were also administered in various combinations. (D) Kaplan-Meier curves comparing overall survival of BPDCN mice models respec- tively treated with vehicle or the above reported treatments. Each treatment is summarized by a box colored as described above. *Indicates that the combination of decitabine and 5’-azacytidine was the most effective in prolonging mice survival. Curves were compared by log-rank test, n=5 mice/treatment arm. (E) Pharmacodynamic assessment of spleen size in 4 representative NSG mice CAL-1 injected after 39 days of treatment with vehicle (mouse Control), Decitabine (mouse Deci), 5’-azacytidine (mouse Aza), and 5’-azacytidine plus decitabine (mouse Deci+Aza) according to the dosing schedule reported above. ns: not significant.
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