%0 Journal Article
%A Vasyutina, E.
%A Boucas, J. M.
%A Bloehdorn, J.
%A Aszyk, C.
%A Crispatzu, G.
%A Stiefelhagen, M.
%A Breuer, A.
%A Mayer, P.
%A Lengerke, C.
%A Döhner, H.
%A Beutner, D.
%A Rosenwald, A.
%A Stilgenbauer, S.
%A Hallek, M.
%A Benner, A.
%A Herling, M.
%T The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL.
%J Leukemia
%V 29
%N 10
%@ 1476-5551
%C Basingstoke
%I Nature Publ. Group
%M DKFZ-2017-03716
%P 2003 - 2014
%D 2015
%X 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 TCL1As 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.
%K Biomarkers, Tumor (NLM Chemicals)
%K DNA-Binding Proteins (NLM Chemicals)
%K MECOM protein, human (NLM Chemicals)
%K MIRN484 microRNA, human (NLM Chemicals)
%K MicroRNAs (NLM Chemicals)
%K Proto-Oncogene Proteins (NLM Chemicals)
%K RNA, Messenger (NLM Chemicals)
%K TCL1A protein, human (NLM Chemicals)
%K Transcription Factors (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:25936528
%R 10.1038/leu.2015.114
%U https://inrepo02.dkfz.de/record/127693