Fig. 4: PIM447 inhibits the aberrant activation of c-MYC and mTOR pathways in cells relying on different JAK/STAT pathway mutations for leukemogenesis. | npj Precision Oncology

Fig. 4: PIM447 inhibits the aberrant activation of c-MYC and mTOR pathways in cells relying on different JAK/STAT pathway mutations for leukemogenesis.

From: PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL

Fig. 4

a Volcano plot showing the results for multiple GSEA-signatures between M07e-JAK3Q988P cells untreated (referred as untreated) and M07e-JAK3Q988P cells treated with PIM447 for 24 hours (referred as PIM447). The selected GSEA-signatures correspond to different signaling pathways that are recurrently deregulated in T-ALL/LBL and whose deregulation may promote tumor development. Those signatures with a confidence rate above 95% are highlighted in red. Data derived from the analysis are shown in the adjacent chart: NES, normalized enrichment score; P, nominal p value; FDR, false discovery rate. b GSEA-plots for c-MYC and mTOR pathways in M07e-JAK3Q988P cells untreated and treated with PIM447. c Western blot for c-NOTCH1, NOTCH1, p-STAT5, STAT5, p-AKT, AKT, p-c-MYC, c-MYC, p-ERK, ERK, p-S6 and S6 in M07e cells transduced with JAK3Q988P untreated or treated with PIM447 (0.1 μM, 1 μM or 10 μM). d Western blot for p-c-MYC, c-MYC, p-S6 and S6 in M07e cells transduced with JAK1V658F or STAT5N642H untreated or treated with PIM447 (0.1 μM, 1 μM or 10 μM). e Western blot for c-NOTCH1, NOTCH1, p-STAT5, STAT5, p-AKT, AKT, p-c-MYC, c-MYC, p-ERK, ERK, p-S6 and S6 in Jurkat cells untreated or treated with PIM447 (0.1 μM, 1 μM or 10 μM). f Western blot for p-c-MYC, c-MYC, p-S6 and S6 in M07e (left) and Ba/F3 cells (right) untransduced (-) or transduced with JAK3WT or JAK3Q988P. g GSEA-plots for c-MYC and mTOR pathways in control thymocytes (referred as thymocytes) and T-ALL/LBL samples with JAK/STAT pathway mutations and a twofold increase in PIM1 expression (referred as JAK/STAT (+) &PIM1(++) samples). We selected human postnatal thymocytes as the most suitable control since T-ALL/LBL samples without mutations in the JAK/STAT pathway may present other molecular alterations that are susceptible of increasing the GSEA-signatures analyzed. All images are representative examples of at least three independent experiments.

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