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000127693 1001_ $$aVasyutina, E.$$b0
000127693 245__ $$aThe regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL.
000127693 260__ $$aBasingstoke$$bNature Publ. Group$$c2015
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000127693 520__ $$aDysregulated T-cell leukemia/lymphoma-1A (TCL1A), a modulator in B-cell receptor (BCR) signaling, is causally implicated in chronic lymphocytic leukemia (CLL). However, the mechanisms of the perturbed TCL1A regulation are largely unknown. To characterize TCL1A-upstream networks, we functionally screened for TCL1A-repressive micro-RNAs (miRs) and their transcriptional regulators. We identified the novel miR-484 to target TCL1As 3-UTR and to be downregulated in CLL. In chromatin immunoprecipitations and reporter assays, the oncogenic transcription factor of myeloid cells, EVI1, bound and activated the miR-484 promoter. Most common in CLL was a pan-EVI1 transcript variant. EVI1 protein expression revealed distinct normal-tissue and leukemia-associated patterns of EVI1/TCL1A co-regulation. EVI1 levels were particularly low in TCL1A-high CLL or such cellular subsets. Global gene expression profiles from a 337-patient set linked EVI1 networks to BCR signaling and cell survival via TCL1A, BTK and other molecules of relevance in CLL. Enforced EVI1, as did miR-484, repressed TCL1A. Furthermore, it reduced phospho-kinase levels, impaired cell survival, mitigated BCR-induced Ca-flux and diminished the in vitro ibrutinib response. Moreover, TCL1A and EVI1 showed a strongly interactive hazard prediction in prospectively treated patients. Overall, we present regressive EVI1 as a novel regulatory signature in CLL. Through enhanced TCL1A and other EVI1-targeted hallmarks of CLL, this contributes to an aggressive cellular and clinical phenotype.
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000127693 650_7 $$2NLM Chemicals$$aBiomarkers, Tumor
000127693 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000127693 650_7 $$2NLM Chemicals$$aMECOM protein, human
000127693 650_7 $$2NLM Chemicals$$aMIRN484 microRNA, human
000127693 650_7 $$2NLM Chemicals$$aMicroRNAs
000127693 650_7 $$2NLM Chemicals$$aProto-Oncogene Proteins
000127693 650_7 $$2NLM Chemicals$$aRNA, Messenger
000127693 650_7 $$2NLM Chemicals$$aTCL1A protein, human
000127693 650_7 $$2NLM Chemicals$$aTranscription Factors
000127693 7001_ $$aBoucas, J. M.$$b1
000127693 7001_ $$aBloehdorn, J.$$b2
000127693 7001_ $$aAszyk, C.$$b3
000127693 7001_ $$aCrispatzu, G.$$b4
000127693 7001_ $$aStiefelhagen, M.$$b5
000127693 7001_ $$aBreuer, A.$$b6
000127693 7001_ $$aMayer, P.$$b7
000127693 7001_ $$aLengerke, C.$$b8
000127693 7001_ $$aDöhner, H.$$b9
000127693 7001_ $$aBeutner, D.$$b10
000127693 7001_ $$aRosenwald, A.$$b11
000127693 7001_ $$aStilgenbauer, S.$$b12
000127693 7001_ $$aHallek, M.$$b13
000127693 7001_ $$0P:(DE-He78)e15dfa1260625c69d6690a197392a994$$aBenner, A.$$b14$$udkfz
000127693 7001_ $$aHerling, M.$$b15
000127693 773__ $$0PERI:(DE-600)2008023-2$$a10.1038/leu.2015.114$$gVol. 29, no. 10, p. 2003 - 2014$$n10$$p2003 - 2014$$tLeukemia$$v29$$x1476-5551$$y2015
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000127693 9141_ $$y2015
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