Results: 4

1.
Figure 1.

Figure 1. From: Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.

PIM kinase expression affects the outcome of lymphoma therapy. (A and B) DLBCL TMAs stained for PIM1 (A) and PIM2 (B). (C and D) Representative tumor cores for each PIM histology score (0–2). (E) Pie graphs showing breakdown of PIM1/2 TMA scores by disease; see also Table S1. (F) TTE analysis after primary therapy in follicular lymphoma (n = 66). (G) OS analysis from date of diagnosis in follicular lymphoma. (H and I) TTE (H) and OS (I) in DLBCL (n = 116).

Jonathan H. Schatz, et al. J Exp Med. 2011 August 29;208(9):1799-1807.
2.
Figure 2.

Figure 2. From: Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.

Pim2 and AKT in a mouse lymphoma model. (A) Eµ-Myc HPCs expressing Pim2, AKT, or vector were transplanted into lethally irradiated syngeneic wild-type mice. Tumor onset in Pim2 (green; n = 12), AKT (red; n = 30) and vector (black; n = 64 recipients). (B) Histological and immunohistochemical analyses of indicated Eµ-Myc lymphomas. Bar, 20 µm. (C) Immunoblot analyses of indicated Eµ-Myc lymphomas. (D–F) Time to relapse in animals bearing Eµ-Myc/Arf−/− (control, black line), Eµ-Myc/Pim2 (green), and Eµ-Myc/AKT (red) lymphomas treated with doxorubicin (D; control, n = 44; Pim2, n = 6; AKT, n = 30) or rapamycin (E; control, n = 27; Pim2, n = 7; AKT, n = 18) or a combination of both drugs (F; control, n = 28; Pim2, n = 13; AKT, n = 21).

Jonathan H. Schatz, et al. J Exp Med. 2011 August 29;208(9):1799-1807.
3.
Figure 4.

Figure 4. From: Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.

The eIF4A helicase inhibitor silvestrol is active against mouse and human lymphomas irrespective of PIM expression. (A) Representative flow cytometry plots showing enrichment of subpopulations of Pim2-GFP–expressing Eµ-Myc/Tsc2−/− upon treatment with vehicle, silvestrol, rapamycin, or silvestrol and rapamycin in vitro. (B) Cumulative analysis of three separate experiments showing mean and SEM. (C) Eµ-Myc/Tsc2−/− and Eµ-Myc/Tsc2−/−/Pim2 cells, or 3T3 fibroblasts or VavP-Bcl2/Myc tumor cells were treated with indicated concentrations of silvestrol. Viability was assessed after 24 h (mean and SEM of 4 separate assays per cell line). (D) Comparison of cell death induced by silvestrol or two PIM kinase inhibitors (SGI-1776, SGI-1773) in a panel of human lymphoma cells (mean of three separate assessments and SEM). (E) Time to relapse in animals bearing Eµ-Myc/Tsc2−/−/Pim2 tumors that were treated with rapamycin (red; n = 9) or rapamycin and silvestrol (green; n = 9), or mice bearing parental Eµ-Myc/Tsc2−/− tumors treated with rapamycin (black dotted line; n = 9). (F and G) Immunoblot on human lymphoma cells Granta-519 (F) or DoHH2 and Su-DHL-10 (G) treated with vehicle (DMSO), the PIM inhibitor SG-1776, or silvestrol.

Jonathan H. Schatz, et al. J Exp Med. 2011 August 29;208(9):1799-1807.
4.
Figure 3.

Figure 3. From: Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.

PIM confers resistance to mTOR inhibition, but not to genetic blockade of cap-dependent translation. (A) Cell viability in vitro comparing rapamycin-sensitive Eµ-Myc/Tsc2−/− lymphomas expressing vector-GFP, Pim1-GFP, or Pim2-GFP under rapamycin treatment. (inset) Enrichment of the Pim2-GFP–expressing subpopulation of Eµ-Myc/Tsc2−/− cells upon rapamycin exposure in vitro. (B) Immunoblot on lysates of Eµ-Myc/Tsc2−/−/vector or Eµ-Myc/Tsc2−/−/Pim2 cells treated with vehicle (U) or rapamycin (R), and probed for the indicated proteins. (C) Polyribosome profiles generated from untreated and rapamycin-treated Eµ-Myc/Tsc2−/− and Eµ-Myc/Tsc2−/−/Pim2 tumors, indicating the ability of PIM2 to stimulate translation in a partially rapamycin-resistant manner (absorbance at 254 nm). (D) Enrichment of populations Eµ-Myc/Tsc2−/− cells expressing vector-GFP (black), Pim2-GFP (orange), and eIF4E-GFP (blue) and treated with rapamycin or the TOR-kinase inhibitors PP-242 and torin (mean fold change and SEM of 5 separate experiments; * indicates significance [P < 0.05] vs. vector). (E) Enrichment or loss of subpopulations of Eµ-Myc/Tsc2−/− and Eµ-Myc/Tsc2−/−/Pim2 cells engineered to express vector encoding GFP or a constitutively active inhibitor of eIF4E (4E-BP1-4A-GFP) during culture in vitro (mean results and SEM of three separate experiments).

Jonathan H. Schatz, et al. J Exp Med. 2011 August 29;208(9):1799-1807.

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