The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is a malignancy of B cells of unknown etiology. Deletions of the chromosomal region 13q14 are commonly associated with CLL, with monoclonal B cell lymphocytosis (MBL), which occasionally precedes CLL, and with aggressive lymphoma, suggesting that this region contains a tumor-suppressor gene. Here, we demonstrate that deletion in mice of the 13q14-minimal deleted region (MDR), which encodes the DLEU2/miR-15a/16-1 cluster, causes development of indolent B cell-autonomous, clonal lymphoproliferative disorders, recapitulating the spectrum of CLL-associated phenotypes observed in humans. miR-15a/16-1-deletion accelerates the proliferation of both human and mouse B cells by modulating the expression of genes controlling cell-cycle progression. These results define the role of 13q14 deletions in the pathogenesis of CLL.
Klein
Ulf
U
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Lia
Marie
M
Crespo
Marta
M
Siegel
Rachael
R
Shen
Qiong
Q
Mo
Tongwei
T
Ambesi-Impiombato
Alberto
A
Califano
Andrea
A
Migliazza
Anna
A
Bhagat
Govind
G
Dalla-Favera
Riccardo
R
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D015139:Blotting, Southern; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014166:Transferases
D035683:MicroRNAs; C544301:Mirn15a microRNA, mouse; C522604:Mirn16 microRNA, mouse; D011506:Proteins; C486375:Dleu2 protein, mouse; D014166:Transferases