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Acute Leukemias

EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia

Abstract

The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia. Expression data from pediatric ALL further suggest that high EVI-1 levels are associated with poor prognosis. Suppression of EVI-1 expression by RNA interference reduces cell growth and enhances apoptosis sensitivity in response to various stimuli in lymphoblastic leukemia cells. At the molecular level, EVI-1 modulates expression of several apoptosis-related genes (such as BCL2, BCL-x, XIAP, NOXA, PUMA, TRAIL-R1). Furthermore, EVI-1 knockdown strongly impairs in vivo engraftment of lymphoblastic leukemia cells upon transplantation in immune-permissive NOD/SCID/IL2Rγnull mice, conferring a survival benefit when compared with mice transplanted with control cells. Thus, our data show that EVI-1 is expressed not only in myeloid but also in lymphoid leukemias, and contributes to the leukemogenic potential and apoptosis resistance of ALL cells.

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Acknowledgements

This study was supported by the Max-Eder Program of the Deutsche Krebshilfe, the Deutsche Forschungsgemeinschaft (SFB773, SFB685, KFO 183/TP4) and the Fortüne Programme of the University of Tuebingen. We thank Claudia Kloss, Sascha Bjoern Fischer and Michael Urschitz for help with histological analyses, FACS analyses and statistical analysis, and Axel Schambach, Maike Stahlhut and Teng Cheong Ha for expression vectors.

Authors contributions

MK, MCA, MG, HW, SG, LQM, OCR and SL designed and performed experiments. CL, MK, MCA, LQM, FE and KSO analyzed results. ME performed the analysis of the pediatric ALL patient cohort. RH, ME, OSK and HRS contributed critical reagents. CL and MK wrote the paper. KSO, MCA, RH, LK, FE, FF and HRS contributed to writing the paper. CL designed the research. All authors contributed to editing of the manuscript.

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Correspondence to C Lengerke.

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Konantz, M., André, M., Ebinger, M. et al. EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia. Leukemia 27, 56–65 (2013). https://doi.org/10.1038/leu.2012.211

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  • DOI: https://doi.org/10.1038/leu.2012.211

Keywords

  • EVI-1
  • acute lymphoblastic leukemia
  • apoptosis
  • ALL
  • NSG mice

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