The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL

• Published in: Leukemia 2015-10, Vol.29 (10), p.2003-2014
• Main Authors: 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, Herling, M
• Format: Article
• Language: English
• Subjects: 13/51; 13/95; 38/109; 38/77; 631/67/1990/283/1895; 692/420/2489/144/68; 692/420/755; 692/699/1541/1990/283/1895; 692/699/67/395; 96/2; 96/31; Apoptosis; B-cell receptor; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Bruton's tyrosine kinase; Cancer Research; Case-Control Studies; Cell Proliferation; Cell survival; Cellular control mechanisms; Cellular signal transduction; Chromatin; Chromatin Immunoprecipitation; Chronic lymphocytic leukemia; Clinical outcomes; Critical Care Medicine; Development and progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Evi1 protein; Flow Cytometry; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Genetic aspects; Genetic regulation; Health aspects; Hematology; Humans; Immunoenzyme Techniques; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphatic leukemia; Lymphocytes B; Lymphocytes T; Lymphoma; MDS1 and EVI1 Complex Locus Protein; Medicine; Medicine & Public Health; MicroRNAs - genetics; Myeloid cells; Oligonucleotide Array Sequence Analysis; Oncogenes; Oncology; original-article; Phenotypes; Prognosis; Properties; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogenes - genetics; Real-Time Polymerase Chain Reaction; Regulators; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Signaling; Survival; Survival Rate; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Cells, Cultured
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.114

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.