13q14 deletions in CLL involve cooperating tumor suppressors.
B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. 13q14 deletions are most common chromosomal alterations in CLL. We previously reported that miR-15/16 is a target of 13q14 deletions and plays a tumor suppressor role by targeting BCL2. Because DLEU7 is located near miR-15/16 and is also positioned within a minimal deleted region, we investigated whether DLEU7 could also play a tumor suppressor role. Recent studies of transgenic mouse models demonstrated the importance of the nuclear factor-kappaB (NF-kappaB) pathway in CLL. To examine the possible role of DLEU7 in CLL, we investigated the effect of DLEU7 expression on NF-kappaB and nuclear factor of activated T cells (NFAT) activity. We found that DLEU7 functions as a potent NF-kappaB and NFAT inhibitor by physically interacting and inhibiting TACI and BCMA, members of the tumor necrosis factor (TNF) receptor family involved in B-CLL. In addition, DLEU7 expression in A549 lung cancer cells resulted in a decrease in S phase and increased apoptosis. The results suggest that loss of DLEU7 may cooperate with the loss of miR-15/16 in the pathogenesis of CLL.
Palamarchuk
Alexey
A
Human Cancer Genetics Program and Comprehensive Cancer Center, Department of Molecular Virology, Immunology and Medical Genetics, School of Medicine, Ohio State University, Columbus, OH, USA
Efanov
Alexey
A
Nazaryan
Natalya
N
Santanam
Urmila
U
Alder
Hansjuerg
H
Rassenti
Laura
L
Kipps
Thomas
T
Croce
Carlo M
CM
Pekarsky
Yuri
Y
D017209:Apoptosis; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D016147:Genes, Tumor Suppressor; D006801:Humans; D047468:Immunoprecipitation; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009363:Neoplasm Proteins; D016196:S Phase; D017384:Sequence Deletion; D014162:Transfection; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D053301:B-Cell Maturation Antigen; C482307:DLEU7 protein, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; C108467:TNFRSF13B protein, human; C086966:TNFRSF17 protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D025521:Tumor Suppressor Proteins; D008156:Luciferases