STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia by Maurizio Mangolini, Jasper de Boer, Vanessa Walf-Vorderwülbecke,

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STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia by Maurizio Mangolini, Jasper de Boer, Vanessa Walf-Vorderwülbecke, Rob Pieters, Monique L. den Boer, and Owen Williams Blood Volume 122(4):542-549 July 25, 2013 ©2013 by American Society of Hematology

Pharmacological and shRNA-mediated inhibition of STAT3 in TEL-AML1 leukemic cells blocks proliferation and induces apoptosis. Pharmacological and shRNA-mediated inhibition of STAT3 in TEL-AML1 leukemic cells blocks proliferation and induces apoptosis. (A-B) Proliferation of leukemic cell lines as measured by MTS assay after 96 hours culture with the indicated concentrations of the STAT3 inhibitor, S3I-301 (A), and STAT5 inhibitor (STAT5in) (B). Results are normalized to the proliferation of dimethylsulfoxide (DMSO)-treated cells. (C) Percentage of apoptotic Annexin V+PI- cells 24 hours after DMSO or S3I-301 treatment. (D) Percentage of cells in the S-phase of the cell-cycle 24 hours after DMSO or S3I-201 exposure. Cells were pulsed with 10 µM 5-ethynyl-2´-deoxyuridine (Edu) for 1 hour. (E) Percentage of apoptotic Annexin V+PI- 6 days after transduction with control scramble or 2 different STAT3 (shSTAT3) shRNA. (F) Percentage of cells in the S-phase of the cell-cycle 6 days after transduction with control scramble or 2 different STAT3 (shSTAT3) shRNA. Cells were pulsed with 10 µM 5-ethynyl-2´-deoxyuridine (Edu) for 1 hour. All data are representative of 3 independent experiments and show mean ± standard deviation of triplicate measurements. *P < .05, **P < .01, ***P < .005 compared with control (Student’s unpaired t test). Maurizio Mangolini et al. Blood 2013;122:542-549 ©2013 by American Society of Hematology

TEL-AML1 induces phosphorylation of STAT3. TEL-AML1 induces phosphorylation of STAT3. (A) Western blot analysis of p-S727 and p-Y705 STAT3 and total STAT3 in mouse c-kit+Ter119- fetal liver HPC, 72 hours after transduction with murine stem cell virus TEL-AML1 expressing (T/A) or empty (MSCV CD2) retroviral vectors. Numbers represent densitometric quantitation of phospho-STAT3 bands normalized to total STAT3. (B) Flow cytometric analysis of p-Y705 STAT3 in Reh 6 days after transduction with control scramble (mean fluorescence intensity [MFI] = 21.04) or shTA shRNA (MFI = 12.01) shRNA. Isotype control staining (MFI = 10.23) is also shown. All data are representative of 3 independent experiments. Maurizio Mangolini et al. Blood 2013;122:542-549 ©2013 by American Society of Hematology

RAC1 is the main STAT3 activator in TEL-AML1 leukemia. RAC1 is the main STAT3 activator in TEL-AML1 leukemia. (A-B) Western blot analysis of GTP-Rac1 pull-downs and total Rac1 from mouse HPC (A), 72 hours after transduction with MSCV T/A or MSCV CD2, and Reh cells (B), 5 days after transduction with control scramble or shTA shRNA. Numbers represent densitometric quantitation of GTP-Rac1 normalized to total RAC1 (A), and GTP-RAC1, and total RAC1 normalized to HSP90 (B). (C) Flow cytometric analysis of p-Y705 STAT3 in Reh, 5 hours after treatment with 50 μM (MFI = 12.99) and 100 μM (MFI = 11.66) NSC23766 or dimethylsulfoxide (MFI = 15.57). (D) Percentage of Reh and At-2 apoptotic Annexin V+PI- cells 24 hours after dimethylsulfoxide or 50 µM NSC23766 treatment. Data are representative of 2 (B) and 3 (A, C, and D) independent experiments. *P < .05, **P < .01, ***P < .005 compared with control (Student unpaired t test). GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Maurizio Mangolini et al. Blood 2013;122:542-549 ©2013 by American Society of Hematology

MYC expression is dependent on TEL-AML1–mediated STAT3 activity. MYC expression is dependent on TEL-AML1–mediated STAT3 activity. (A) Quantitative reverse-transcription polymerase chain reaction analysis of MYC mRNA expression 6 hours after treatment with 50 µM S3I-201, 50 µM NSC23766, or dimethylsulfoxide in Reh, At-2, and 697 cells. Columns represent mean ± standard deviation of quadruplicate measurements. (B-E) Western blot analysis of MYC protein expression in Reh and At-2 cells 24 hours after treatment with 50 µM S3I-201 (B), or 50 µM NSC23766 (C), or 6 days after transduction with control scramble, STAT3 (shSTAT3) shRNA (D), or shTA shRNA (E). Numbers represent densitometric quantitation of MYC bands normalized to GAPDH (B-D) and HSP90 (E). Percentage of apoptotic Annexin V+PI- cells (F) and S-phase cells (G) 6 days after transduction with scramble or 2 different MYC (shMYC) shRNA. Data are representative of 2 (D) and 3 (A-G) independent experiments and show mean ± standard deviation of triplicate measurements. *P < .05, **P < .01, ***P < .005 compared with control (Student unpaired t test). GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Maurizio Mangolini et al. Blood 2013;122:542-549 ©2013 by American Society of Hematology

STAT3 is necessary for colony formation by TEL-AML1+ cells. STAT3 is necessary for colony formation by TEL-AML1+ cells. (A-C) Colony formation in methylcellulose by Reh cells 6 days after transduction with control scramble or shTA (A), shSTAT3 (B), or shMYC (C) shRNA. Plots show the number of colonies formed relative to control cultures, columns representing mean ± standard deviation values of triplicate cultures. Data are representative of 3 independent experiments. **P < .01, ***P < .005 compared with control (Student unpaired t test). CFU, colony-forming unit. Maurizio Mangolini et al. Blood 2013;122:542-549 ©2013 by American Society of Hematology

Leukemia progression of TEL-AML1+ cell lines and survival of t(12;21) primary leukemia cells is impaired by STAT3 inhibition. Leukemia progression of TEL-AML1+ cell lines and survival of t(12;21) primary leukemia cells is impaired by STAT3 inhibition. Leukemia progression of TEL-AML1+ cell lines and survival of t(12;21) primary leukemia cells is impaired by STAT3 inhibition. (A) Kaplan-Meier survival curve for NSG mice transplanted with control scramble (n = 7) or shSTAT3 (n = 8) transduced Reh cells. P = .0002 versus scramble control (Mantel-Cox log-rank test). (B) Viability as measured by MTS assay of 4 independent TEL-AML1+ primary human leukemic samples after treatment with different S3I-201 concentrations for 96 hours. The response of Reh cells is included as a reference (C). Percentage apoptosis of 2 different primary human leukemic samples after 24-hour exposure to 50 µM S3I-201. (D) Western blot analysis of MYC protein expression in primary cells 24 hours after treatment with 50 µM S3I-201. **P < .01, ***P < .005 compared with control (Student unpaired t test). DMSO, dimethylsulfoxide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Maurizio Mangolini et al. Blood 2013;122:542-549 ©2013 by American Society of Hematology

Model of TEL-AML1–induced leukemogenesis. Model of TEL-AML1–induced leukemogenesis. TEL-AML1 induces RAC1 activation that, in turn, promotes STAT3 phosphorylation and consequently the induction of MYC transcription. Active STAT3 is necessary for the survival, proliferation, and self-renewal of TEL-AML1expressing ALL cells. Maurizio Mangolini et al. Blood 2013;122:542-549 ©2013 by American Society of Hematology