miR-15b/16-2 deletion promotes B-cell malignancies.
The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over two-thirds of B-cell chronic lymphocytic leukemia characterized by the deletion of the miR-15a/16-1 locus at 13q14. Despite the well-established understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster's role in vivo. These mice developed B-cell malignancy by age 15-18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
Francesca
F
Lovat
Surgical Pathology and Cytopathology Unit, Department of Medicine, University of Padua, Padua 35121, Italy; Applied Research on Cancer Network (ARC-NET) Research Centre, University of Verona, Verona 37126, Italy;
Matteo
M
Fassan
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
Pierluigi
P
Gasparini
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
Lara
L
Rizzotto
Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Bellinzona 6500, Switzerland.
Luciano
L
Cascione
Surgical Pathology and Cytopathology Unit, Department of Medicine, University of Padua, Padua 35121, Italy;
Marco
M
Pizzi
Applied Research on Cancer Network (ARC-NET) Research Centre, University of Verona, Verona 37126, Italy;
Caterina
C
Vicentini
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
Veronica
V
Balatti
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
Dario
D
Palmieri
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
Stefan
S
Costinean
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; carlo.croce@osumc.edu.
Carlo M
CM
Croce
D000818:Animals; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2 / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics
C530105:Ccnd1 protein, mouse; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; C522604:Mirn16 microRNA, mouse; D019938:Cyclin D1; D017526:Receptor, IGF Type 1
B cells; chronic lymphocytic leukemia; miR-15b; miRNAs; murine models