Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia by Shannon L. Maude, Sibasish.

Slides:

Advertisements

Similar presentations

Figure 6. Effect of Withaferin A (WA) treatment on leptin-induced signaling in breast cancer cells. A) Immunoblotting for pSTAT3 (Tyr705), total STAT3,

Advertisements

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

Involvement of suppressors of cytokine signaling in toll-like receptor–mediated block of dendritic cell differentiation by Holger Bartz, Nicole M. Avalos,

IFN-γ and STAT1 are required for efficient induction of CXC chemokine receptor 3 (CXCR3) on CD4+ but not CD8+ T cells by Joseph Barbi, Steve Oghumu, Claudio.

Interleukin-5–producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy by Frédéric Van Gool, Ari B. Molofsky, Malika.

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency by Tayebeh Soheili, Amandine Durand, Fernando.

Differential STAT3, STAT5, and NF-κB activation in human hematopoietic progenitors by endogenous interleukin-15: implications in the expression of functional.

Involvement of casein kinase Iϵ in cytokine-induced granulocytic differentiation by Atsuo Okamura, Nobuko Iwata, Aki Nagata, Akira Tamekane, Manabu Shimoyama,

A novel TNFR1-triggered apoptosis pathway mediated by class IA PI3Ks in neutrophils by Barbara Geering, Ursina Gurzeler, Elena Federzoni, Thomas Kaufmann,

CD154 Expression Is Associated with Neutralizing Antibody Titer Levels Postinfluenza Vaccination in Stem Cell Transplant Patients and Healthy Adults

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)‏ by David T. Teachey, Dana A. Obzut, Kelly Axsom,

Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines by Xiao-Fang.

by Daniel Sasca, Patricia S

Retinoic acid–induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional.

Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo by Min.

In the absence of IGF-1 signaling, IFN-γ suppresses human malignant T-cell growth by Laura Conti, Gabriella Regis, Angela Longo, Paola Bernabei, Roberto.

by Christopher J. Ott, Nadja Kopp, Liat Bird, Ronald M

Metalloproteinases Are Involved in Lipopolysaccharide– and Tumor Necrosis Factor-–Mediated Regulation of CXCR1 and CXCR2 Chemokine Receptor Expression.

The tyrosine phosphatase SHP-1 dampens murine Th17 development

CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy.

Inhibition of Th1 Differentiation by IL-6 Is Mediated by SOCS1

Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation by Shiguo Zhu, Prasad V. Phatarpekar,

TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS by Dhifaf Sarhan, Ludwig Brandt, Martin Felices, Karolin Guldevall,

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia by Donya Moradi Manesh, Jad El-Hoss, Kathryn.

by Éric Aubin, Réal Lemieux, and Renée Bazin

Preactivation with IL-12, IL-15, and IL-18 Induces CD25 and a Functional High-Affinity IL-2 Receptor on Human Cytokine-Induced Memory-like Natural Killer.

Surface IgM stimulation induces MEK1/2-dependent MYC expression in chronic lymphocytic leukemia cells by Sergey Krysov, Samantha Dias, Alex Paterson, C.

Altered interferon signaling with JAK1 loss-of-function mutation in M431 and interferon gamma-inducible PD-L1 expression by 48 melanoma cell lines. Altered.

Vascular endothelial growth factor stimulates protein kinase CβII expression in chronic lymphocytic leukemia cells by Simon T. Abrams, Benjamin R. B. Brown,

IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis

by Zhihong Zeng, Dos D. Sarbassov, Ismael J. Samudio, Karen W. L

LPS induces CD40 gene expression through the activation of NF-κB and STAT-1α in macrophages and microglia by Hongwei Qin, Cynthia A. Wilson, Sun Jung Lee,

Ubiquitination and degradation of the thrombopoietin receptor c-Mpl

Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function by Vânia Coelho, Sergey Krysov, Andrew.

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells by Bing Z. Carter, Marcela Gronda,

Generation of Highly Cytotoxic Natural Killer Cells for Treatment of Acute Myelogenous Leukemia Using a Feeder-Free, Particle-Based Approach Jeremiah.

Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells by Uri Rozovski, Ji Yuan Wu, David.

STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells by Daniel Ribeiro, Alice Melão,

Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells by Jonathan M. Irish,

Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival by Kyu-Tae Kim, Kristin Baird, Joon-Young Ahn, Paul.

Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia by Shahrzad Jalali, Tammy Price-Troska, Jonas Paludo, Jose Villasboas, Hyo-Jin.

Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia by Parvathi Ranganathan, Xueyan Yu, Caroline Na, Ramasamy Santhanam, Sharon Shacham,

Miriam Wittmann, MD, Jana Zeitvogel, Dong Wang, MD, Thomas Werfel, MD

MiR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53 by Francisco Navarro, David Gutman, Eti Meire, Mario Cáceres,

Inhibition of human B-cell development into plasmablasts by histone deacetylase inhibitor valproic acid Anne-Kathrin Kienzler, MSc, Marta Rizzi, MD,

by Kamira Maharaj, John J

by Silvia Mele, Stephen Devereux, Andrea G

Autocrine IL-21 Stimulation Is Involved in the Maintenance of Constitutive STAT3 Activation in Sézary Syndrome Leslie van der Fits, Jacoba J. Out-Luiting,

The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy by Suhu Liu, Anna E. Marneth, Gabriela.

WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice by Marcela Gatica-Andrades, Dimitrios.

Volume 132, Issue 5, Pages (May 2007)

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations Giovanna.

Oncogenic role and therapeutic targeting of ABL-class and JAK-STAT activating kinase alterations in Ph-like ALL by Kathryn G. Roberts, Yung-Li Yang, Debbie.

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

Defective negative regulation of Toll-like receptor signaling leads to excessive TNF-α in myeloproliferative neoplasm by Hew Yeng Lai, Stefan A. Brooks,

Volume 5, Issue 1, Pages (July 2009)

by Shannon L. Maude, David T. Teachey, David L. Porter, and Stephan A

Targeting ubiquitin-activating enzyme induces ER stress–mediated apoptosis in B-cell lymphoma cells by Scott Best, Taylor Hashiguchi, Adam Kittai, Nur.

by Rodrigo Abreu, Frederick Quinn, and Pramod K. Giri

AML cells display differential sensitivity to inhibition of IKBKE and TBK1. AML cells display differential sensitivity to inhibition of IKBKE and TBK1.

by Pamela J. Sung, Mayumi Sugita, Holly Koblish, Alexander E

IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells by Ana Camelo, Guglielmo Rosignoli, Yoichiro.

Senescence-associated defective HLA-DR upregulation does not modulate immunosuppressive properties of MSCs. (A) Fit and senescent MSCs were subjected to.

Treatment effects of fenretinide (4-HPR, 5 μmol/L), 2-ME (2

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma by Bethany Mundy-Bosse, Nathan Denlinger,

ALT-803 stimulates proliferation and activation of human NK cells and T cells in vitro. ALT-803 stimulates proliferation and activation of human NK cells.

by Geoffrey A. Smith, Jack Taunton, and Arthur Weiss

by Dana S. Levy, Jason A. Kahana, and Rakesh Kumar

by Wolfgang Warsch, Christoph Walz, and Veronika Sexl

In vivo efficacy of JAK inhibition in transformed Pax5+/− pro-B cells harboring Jak3V670A. In vivo efficacy of JAK inhibition in transformed Pax5+/− pro-B.

Presentation transcript:

Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia by Shannon L. Maude, Sibasish Dolai, Cristina Delgado-Martin, Tiffaney Vincent, Alissa Robbins, Arthavan Selvanathan, Theresa Ryan, Junior Hall, Andrew C. Wood, Sarah K. Tasian, Stephen P. Hunger, Mignon L. Loh, Charles G. Mullighan, Brent L. Wood, Michelle L. Hermiston, Stephan A. Grupp, Richard B. Lock, and David T. Teachey Blood Volume 125(11):1759-1767 March 12, 2015 ©2015 by American Society of Hematology

Increased JAK/STAT activation in ETP-ALL relative to non-ETP T-ALL. Increased JAK/STAT activation in ETP-ALL relative to non-ETP T-ALL. (A) Levels of phosphophorylated (p) and total signaling pathway proteins in the spleens of non-ETP T-ALL xenograft models (ALL8, ALL16, ALL29, ALL30, ALL31, ALL33) and ETP-ALL xenograft models (ETP1, ETP5, ETP8, ETP12, ETP13, ETP14) by immunoblot. A CRLF2-overexpressing B-ALL xenograft with high levels of JAK/STAT pathway proteins was used as a positive control (Control). (B) Comparison of levels of pSTATs and Bcl-2 in non-ETP T-ALL and ETP-ALL xenografts. Protein levels by immunoblot of 3 replicates were quantitated relative to positive control (Control), graphed as means, and analyzed using the nonparametric Mann-Whitney test. Shannon L. Maude et al. Blood 2015;125:1759-1767 ©2015 by American Society of Hematology

ETP-ALL hypersensitivity to IL7 stimulation. ETP-ALL hypersensitivity to IL7 stimulation. (A) Phosphoflow cytometry analysis of levels of pSTAT5 in xenografted non-ETP T-ALL and ETP-ALL leukemic blasts in the basal state (shaded) and in response to stimulation with 100 ng/mL IL7 for 15 minutes (unshaded). (B) Quantitation of mean fluorescence intensity (MFI) in the basal state and in response to IL7 exposure. (C) Change in pSTAT5 MFI with IL7 exposure compared with vehicle treatment of each xenograft. The nonparametric Mann Whitney test was used to evaluate statistical significance. Shannon L. Maude et al. Blood 2015;125:1759-1767 ©2015 by American Society of Hematology

Expression of the IL7 receptor, CD127, correlates with IL7-induced STAT5 phosphorylation. Expression of the IL7 receptor, CD127, correlates with IL7-induced STAT5 phosphorylation. Flow cytometry analysis of surface CD127 expression. Quantitation of MFI in non-ETP T-ALL samples that did or did not respond to IL7 and in ETP-ALL samples. Shannon L. Maude et al. Blood 2015;125:1759-1767 ©2015 by American Society of Hematology

Ruxolitinib abrogates IL7-induced STAT5 phosphorylation. Ruxolitinib abrogates IL7-induced STAT5 phosphorylation. (A) ETP-ALL xenograft samples were treated for 30 minutes with vehicle (shaded) or 500 nM ruxolitinib (unshaded), and pSTAT5 levels were assessed by flow cytometry. (B) ETP-ALL xenograft samples treated as in A were subsequently exposed to vehicle or 100 ng/mL IL7 for 20 minutes, and pSTAT levels were measured. Shannon L. Maude et al. Blood 2015;125:1759-1767 ©2015 by American Society of Hematology

Efficacy of ruxolitinib in xenograft models of ETP-ALL. Efficacy of ruxolitinib in xenograft models of ETP-ALL. Peripheral blood blast count over time and splenic blast count at death in ETP-ALL xenografts. Graphed are means and standard deviations with absolute blast count on the vertical axis and days of treatment on the horizontal axis. Shannon L. Maude et al. Blood 2015;125:1759-1767 ©2015 by American Society of Hematology

Down-regulation of JAK targets with ruxolitinib treatment. Down-regulation of JAK targets with ruxolitinib treatment. Levels of phosphophorylated (p) and total STAT proteins in the spleens of ETP-ALL xenografts. Xenografts (2-3 mice per arm, replicates shown) were treated with ruxolitinib (rux) or vehicle (con) for 72 hours, spleens were harvested, and protein lysates were subjected to immunoblot. Protein levels by immunoblot of replicates were quantitated relative to actin and analyzed by the Welch-Satterthwaite t test. Levels of pSTAT1 were reduced by >50% in treated mice compared with control for all 6 samples (P < .05). There was a >50% reduction in pSTAT3, which was statistically significant (P < .05) for ETP1, 5, 8, and 14 but not significant for ETP12 and 13. There was a 70% or greater reduction in pSTAT5 for all 6 samples (P < .05). Shannon L. Maude et al. Blood 2015;125:1759-1767 ©2015 by American Society of Hematology