title: MicroRNA and proliferation control in chronic lymphocytic leukemia: functional relationship between miR-221/222 cluster and p27.
abstract: We investigated functional relationships between microRNA 221/222 (miR-221/222) cluster and p27, a key regulator of cell cycle, in chronic lymphocytic leukemia (CLL). The enforced expression of miR-221/222 in the CLL cell line MEC1 induced a significant down-regulation of p27 protein and conferred a proliferative advantage to the transduced cells that exhibited faster progression into the S phase of the cell cycle. Accordingly, expression of miR-221/miR-222 and p27 was found to be inversely related in leukemic cells obtained from peripheral blood (PB) of 38 patients with CLL. Interestingly, when miR-221/222 and p27 protein were evaluated in different anatomic compartments (lymph nodes or bone marrow) of the same patients, increased expression of the 2 miRNAs became apparent compared with PB. This finding was paralleled by a low expression of p27. In addition, when CLL cells were induced in vitro to enter cell cycle (eg, with cytosine phosphate guanine oligodeoxynucleotide), a significant increase of miR-221/222 expression and a marked down-regulation of p27 protein were evident. These data indicate that the miR-221/222 cluster modulates the expression of p27 protein in CLL cells and lead to suggest that miR-221/222 and p27 may represent a regulatory loop that helps maintaining CLL cells in a resting condition.
authors.affiliation: Department of Oncology, Unit and Laboratory of Lymphoid Malignancies, San Raffaele Scientific Institute and Universita Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Frenquelli
authors.forename: Marta
authors.initials: M
authors.lastname: Muzio
authors.forename: Cristina
authors.initials: C
authors.lastname: Scielzo
authors.forename: Claudia
authors.initials: C
authors.lastname: Fazi
authors.forename: Lydia
authors.initials: L
authors.lastname: Scarfò
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ferrari
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D035683:MicroRNAs; D012333:RNA, Messenger; C525709:MIR221, human; C525710:MIR222, human