TY  - JOUR
AU  - Vasyutina, E.
AU  - Boucas, J. M.
AU  - Bloehdorn, J.
AU  - Aszyk, C.
AU  - Crispatzu, G.
AU  - Stiefelhagen, M.
AU  - Breuer, A.
AU  - Mayer, P.
AU  - Lengerke, C.
AU  - Döhner, H.
AU  - Beutner, D.
AU  - Rosenwald, A.
AU  - Stilgenbauer, S.
AU  - Hallek, M.
AU  - Benner, A.
AU  - Herling, M.
TI  - The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL.
JO  - Leukemia
VL  - 29
IS  - 10
SN  - 1476-5551
CY  - Basingstoke
PB  - Nature Publ. Group
M1  - DKFZ-2017-03716
SP  - 2003 - 2014
PY  - 2015
AB  - 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.
KW  - Biomarkers, Tumor (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - MECOM protein, human (NLM Chemicals)
KW  - MIRN484 microRNA, human (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - Proto-Oncogene Proteins (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - TCL1A protein, human (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25936528
DO  - DOI:10.1038/leu.2015.114
UR  - https://inrepo02.dkfz.de/record/127693
ER  -