The regulatory interaction of evi1 with the tcl1a oncogene impacts cell survival and clinical outcome in cll

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. Access through your institution Buy or subscribe This is a preview of subscription content,

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Article  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * 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 * Department of Internal Medicine III, Ulm University,

Ulm, Germany J Bloehdorn, H Döhner & S Stilgenbauer * Department of Hematology and Oncology, University of Tübingen Medical Center II, Tübingen, Germany C Lengerke * Department of

Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany D Beutner * Institute of Pathology, University of Würzburg, Würzburg, Germany A Rosenwald * Division of

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 01 March 2015 * Accepted: 20 April 2015 * Published: 04 May 2015

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