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mTORi unlocks AML resistance to LSD1i
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Figure 7. Targeting mTOR sensitizes primary patient-derived MLL-AF9 expressing (AML-IEO20) leukemia blasts to LSD1 inhibition in vitro and in vivo. (A) Schematic outline of the in vivo stud- ies with the PDX model of AML-IEO20 leukemia. (B-I) Flow cytometric analyses of the percent of human CD45+ leukemic cells in the peripheral blood (PB) obtained from NSG mice transplanted with primary human AML-IEO20 cells and treated for 7 (B), 14 (C), 21 (G) and 28 (H) days with either: vehicle (Veh), DDP38003 (DDP, 16.8 mg/kg, PO), rapamycin (Rapa, 5 mg/kg, IP) or DDP38003 + rapamycin. (D) Effect of different treatments on the spleen index following 15 days of treatment. Data were statistically analyzed using one-way ANOVA followed by Tukey-Kramer post hoc test. a,b,c: P<0.05 compared to non-transplanted and vehicle-treated and DDP38003 alone xenotransplanted groups respectively. Upper right panel: image of spleens harvested from NSG mice 15 days following their treatment with either vehicle or DDP38003 or rapamycin or a combination of DDP38003 and rapamycin (n=2/group). (E-F) Flowcytometric analysis of AML- IEO20 leukemic engraftment depicted as percent of human CD45+ leukemic cells in the spleen (E) and bone marrow (F) after 15 days of treatment initiation (n=2/group). Data were statistical- ly analyzed using one-way ANOVA followed by Tukey-Kramer post hoc test. *: P<0.05. Data rep- resents mean ± standard deviation (SD). Data were statistically analyzed using one-way ANOVA followed by Tukey-Kramer post hoc test. *: P<0.05. (I) Flow cytometric analyses of the percent of human CD45+ leukemic cells in peripheral blood obtained from NSG mice transplanted with primary human AML-IEO20 cells and treated for the indicated time points with either: vehicle, DDP38003, rapamycin or their combination. (J) Kaplan Meier survival curve of mice engrafted with primary AML-IEO20 cells treated with vehicle, DDP38003, rapamycin or DDP38003 + rapamycin. Statistical significance was evaluated using log-rank (Mantel-Cox’s) test. a,b,c: P<0.05 compared to vehicle, DDP38003 or rapamycin-only treated groups respectively. (K) Schematic representation of the proposed mechanism by which modulation of IRS1/ERK/mTOR signaling governs the sensitivity/resistance of acute myeloid leukemia (AML) cells to LSD1 inhibition (LSD1i).
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