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Chronic lymphocytic leukemia

The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL

Leukemia volume 29, pages 2003–2014 (2015)Cite this article

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Abstract

Dysregulated T-cell leukemia/lymphoma-1A (TCL1A), a modulator in B-cell receptor (BCR) signaling, is causally implicated in chronic lymphocytic leukemia (CLL). However, the mechanisms of the perturbed TCL1A regulation are largely unknown. To characterize TCL1A-upstream networks, we functionally screened for TCL1A-repressive micro-RNAs (miRs) and their transcriptional regulators. We identified the novel miR-484 to target TCL1A’s 3′-UTR and to be downregulated in CLL. In chromatin immunoprecipitations and reporter assays, the oncogenic transcription factor of myeloid cells, EVI1, bound and activated the miR-484 promoter. Most common in CLL was a pan-EVI1 transcript variant. EVI1 protein expression revealed distinct normal-tissue and leukemia-associated patterns of EVI1/TCL1A co-regulation. EVI1 levels were particularly low in TCL1A-high CLL or such cellular subsets. Global gene expression profiles from a 337-patient set linked EVI1 networks to BCR signaling and cell survival via TCL1A, BTK and other molecules of relevance in CLL. Enforced EVI1, as did miR-484, repressed TCL1A. Furthermore, it reduced phospho-kinase levels, impaired cell survival, mitigated BCR-induced Ca-flux and diminished the in vitro ibrutinib response. Moreover, TCL1A and EVI1 showed a strongly interactive hazard prediction in prospectively treated patients. Overall, we present regressive EVI1 as a novel regulatory signature in CLL. Through enhanced TCL1A and other EVI1-targeted hallmarks of CLL, this contributes to an aggressive cellular and clinical phenotype.

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Acknowledgements

We acknowledge the help in CLL sample acquisition by T Landwehr of the Biobank of the Center of Integrated Oncology Cologne-Bonn funded by the German Cancer Aid. The German Cancer Aid primarily supported this work by a Max-Eder award to MHe. The Köln Fortune Program provided start-up funds to EV. Funding by the CECAD initiative supported MHa and MHe. MHe also receives support by the German Research Foundation (DFG) under HE-3553/3-1 as part of the collaborative research group KFO-286. SS receives project-relevant funding from the DFG (SFB1074, project B2), the Else-Kröner-Fresenius-Stiftung (2012_A146) and from F Hoffmann-La Roche.

Author Contributions

EV, JMB and MHe designed the experiments and analyzed the in vitro generated data. EV, JMB, ABr, CA and PM performed the in vitro experiments. JB performed gene expression profiling. Statistical data analysis on the CLL8 trial data set was performed by JB, GC, EV (gene expression, GSOA, heat-map generation) and by ABe (clinical and outcome associations). JB, MS, CL, ABe, HD, SS, MHa and MHe collected the clinical data. DB and AR acquired tissue samples, assisted in histological stainings and analyzed read-outs. EV, ABe and MHe wrote the manuscript.

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Authors and Affiliations

  1. Department I of Internal Medicine, Center for Integrated Oncology Cologne-Bonn, and Excellence Cluster for Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany

    E Vasyutina, J M Boucas, C Aszyk, G Crispatzu, M Stiefelhagen, A Breuer, P Mayer, M Hallek & M Herling

  2. Department of Internal Medicine III, Ulm University, Ulm, Germany

    J Bloehdorn, H Döhner & S Stilgenbauer

  3. Department of Hematology and Oncology, University of Tübingen Medical Center II, Tübingen, Germany

    C Lengerke

  4. Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany

    D Beutner

  5. Institute of Pathology, University of Würzburg, Würzburg, Germany

    A Rosenwald

  6. Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany

    A Benner

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  1. E Vasyutina
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Correspondence to M Herling.

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Vasyutina, E., Boucas, J., Bloehdorn, J. et al. The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL. Leukemia 29, 2003–2014 (2015). https://doi.org/10.1038/leu.2015.114

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