title: Activation of miR-17-92 by NK-like homeodomain proteins suppresses apoptosis via reduction of E2F1 in T-cell acute lymphoblastic leukemia.
abstract: The NK-like family of homeobox genes includes TLX1, TLX3 and NKX2-5, which are ectopically activated in distinct subsets of T-cell acute lymphoblastic leukemia (T-ALL) cells. Here we analysed their effect on the miR-17-92 cluster overexpressed in several types of cancer, including T-ALL. The pri-miR-17-92 polycistron encodes micro-RNAs (miRNAs), which decrease E2F1 protein expression, regulating proliferation and/or apoptosis. Quantification of pri-miR-17-92 in T-ALL cell lines suggested an implication of the NK-like homeodomain proteins in transcriptional regulation. Lentiviral-mediated overexpression of NKX2-5 in the T-ALL cell line MOLT-4 consistently resulted in increased miR-17-92 pri-miRNA levels and decreased amounts of E2F1 protein. Induction of apoptosis by treating miR17-92 or E2F1 transduced T-ALL cells with etoposide led to reduced or enhanced cell viability, respectively. Furthermore, analysis of pri-miR-17-92 in T-ALL patients indicated elevated expression in those bearing TLX1/3 positive cells. These data support an activatory effect of NK-like homeodomain proteins on pri-miR-17-92 expression and concomitantly reduced E2F1 protein levels, thereby enhancing survival of leukemic T-cells.
authors.affiliation: Department of Human and Animal Cell Cultures, DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. sna@dsmz.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.forename: Letizia
authors.initials: L
authors.lastname: Venturini
authors.forename: Grzegorz K
authors.initials: GK
authors.lastname: Przybylski
authors.forename: Piotr
authors.initials: P
authors.lastname: Grabarczyk
authors.forename: Christian A
authors.initials: CA
authors.lastname: Schmidt
authors.forename: Corinna
authors.initials: C
authors.lastname: Meyer
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: Macleod
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D050687:E2F1 Transcription Factor; D018398:Homeodomain Proteins; D035683:MicroRNAs