Activation of miR-17-92 by NK-like homeodomain proteins suppresses apoptosis via reduction of E2F1 in T-cell acute lymphoblastic leukemia.
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.
Nagel
Stefan
S
Department of Human and Animal Cell Cultures, DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. sna@dsmz.de
Venturini
Letizia
L
Przybylski
Grzegorz K
GK
Grabarczyk
Piotr
P
Schmidt
Christian A
CA
Meyer
Corinna
C
Drexler
Hans G
HG
Macleod
Roderick A F
RA
Scherr
Michaela
M
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*
D050687:E2F1 Transcription Factor; D018398:Homeodomain Proteins; D035683:MicroRNAs