Ppm1d mediates sensitivity of primary leukemia cells to cytotoxic agents. (A) Schematic of generation of primary leukemia cells using viral transduction of MLL-AF9-GFP into c-kit-enriched bone marrow from Ppm1d+/+;Vav-Cre+ (WT), Ppm1dfl/fl;Vav-Cre+ (KO), or Ppm1dT476∗-fl/+;Vav-Cre+ (TR) mice and transplantation into sublethally irradiated recipients. (B) Frequency of Ppm1dT476∗-fl/+ leukemia cells when grown with Ppm1d+/+ leukemia cells in vitro over a 10-day period in the presence of dimethyl sulfoxide (DMSO) (no drug), GSK2830371, Cisplatin, or Cisplatin and GSK2830371 (supplemental Figure 4A). (C-E) Viability of primary leukemia cells, as assessed using CellTiterGlo, after 3 days of in vitro exposure to cytotoxic therapies (B), GSK2830371 (C), or both (D). Representative figures from one of the biological replicates is shown here. (F-G) Schematic (F) and survival (G) of mice carrying MLL-AF9+ leukemias treated with vehicle, GSK283071, doxorubicin with Ara-C (“5 + 3”), or doxorubicin with Ara-C and GSK2830371 (“5 + 3 + GSK”). Error bars show SEM, ∗P < .01, ∗∗P < .001.
