Journal Article

DKFZ-2017-03716

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL.

Vasyutina, E. ; Boucas, J. M. ; Bloehdorn, J. ; Aszyk, C. ; Crispatzu, G. ; Stiefelhagen, M. ; Breuer, A. ; Mayer, P. ; Lengerke, C. ; Döhner, H. ; Beutner, D. ; Rosenwald, A. ; Stilgenbauer, S. ; Hallek, M. ; Benner, A.DKFZ* ; Herling, M.

2015
Nature Publ. Group Basingstoke

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Please use a persistent id in citations: doi:10.1038/leu.2015.114

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 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.

Keyword(s): Biomarkers, Tumor ; DNA-Binding Proteins ; MECOM protein, human ; MIRN484 microRNA, human ; MicroRNAs ; Proto-Oncogene Proteins ; RNA, Messenger ; TCL1A protein, human ; Transcription Factors

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Contributing Institute(s):

1. Biostatistik (C060)

Research Program(s):

1. 313 - Cancer risk factors and prevention (POF3-313) (POF3-313)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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