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With me or against me: Tumor suppressor and drug resistance activities of SAMHD1  Nikolas Herold, Sean G. Rudd, Kumar Sanjiv, Juliane Kutzner, Ida Hed.

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Presentation on theme: "With me or against me: Tumor suppressor and drug resistance activities of SAMHD1  Nikolas Herold, Sean G. Rudd, Kumar Sanjiv, Juliane Kutzner, Ida Hed."— Presentation transcript:

1 With me or against me: Tumor suppressor and drug resistance activities of SAMHD1 
Nikolas Herold, Sean G. Rudd, Kumar Sanjiv, Juliane Kutzner, Ida Hed Myrberg, Cynthia B.J. Paulin, Thale Kristin Olsen, Thomas Helleday, Jan-Inge Henter, Torsten Schaller  Experimental Hematology  Volume 52, Pages (August 2017) DOI: /j.exphem Copyright © 2017 ISEH - International Society for Experimental Hematology Terms and Conditions

2 Figure 1 The double-edged sword of SAMHD1's role in tumorigenesis and drug resistance. High levels of SAMHD1 (on the right) are associated with increased substrate hydrolysis and lower cellular dNTP levels, which contribute to the turnover of nucleoside-based antimetabolite triphosphates (e.g., ara-CTP) and are associated with reduced cytotoxicity of these drugs. In contrast, low SAMHD1 expression, for example, by promoter methylation (on the left), is associated with reduced dNTP hydrolysis and increased dNTP levels, contributing to tumorigenesis. Experimental Hematology  , 32-39DOI: ( /j.exphem ) Copyright © 2017 ISEH - International Society for Experimental Hematology Terms and Conditions

3 Figure 2 SAMHD1−/− tumors are hypersensitive to ara-C treatment in vivo. In an orthotopic mouse model, animals were injected in the tail vein with 5 × 106 THP-1 cells expressing wild-type SAMHD1 or with SAMHD1−/− cells as described [36,52]. Prior to transplantation, cells were transduced with the lentiviral vector pCSxW [36] expressing amino-terminal HA-tagged firefly luciferase at an estimated multiplicity of infection of 100. On day 6 after transplantation, mice were treated with 100 mg/kg ara-C (dissolved in PBS at 20 mg/mL) intraperitoneally, daily for 5 consecutive days. Study endpoints have been described [36,52]. (A) Kaplan–Meier survival analysis. A Mantel–Cox log–rank test was performed using Prism 7 (GraphPad). (B) Tumor growth was monitored by measuring luciferase activity 10 min after intraperitoneal application of 10 mg/kg of a D-luciferin stock of 15 mg/mL dissolved in PBS (Sigma-Aldrich) using an IVIS SpectrumCT in vivo imaging system (Perkin-Elmer). Experimental Hematology  , 32-39DOI: ( /j.exphem ) Copyright © 2017 ISEH - International Society for Experimental Hematology Terms and Conditions

4 Figure 3 Time-dependent hazard rates for SAMHD1 mRNA expression in the TCGA AML cohort. Cox proportional hazards models were used to assess the association between log-transformed SAMHD1 mRNA and survival ([A] EFS and [B] OS, respectively) in ara-C–treated AML patients from the TCGA cohort as described [36]. The standardized Shoenfeld residuals were plotted against a log transformation of time to event, to evaluate the possible time-dependent effect of SAMHD1 mRNA expression levels. A time-dependent coefficient was added to the models, using restricted cubic splines with 3 knots as a transformation of the time-variable, times log-transformed SAMHD1 mRNA. Positive β values (y-axis) indicate hazard rates >1; negative β values indicate hazard rates <1. The package “survival” in R Version was used for all statistical analyses. Area in between dotted lines indicates 95% confidence interval (p ≤ 0.05). Experimental Hematology  , 32-39DOI: ( /j.exphem ) Copyright © 2017 ISEH - International Society for Experimental Hematology Terms and Conditions


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