LNA-mediated anti-miR-155 silencing in low-grade B-cell lymphomas.
miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155-based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti-miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti-miR-155 delivered systemically showed uptake in the BM CD19(+) cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155-knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti-miR-155-mediated inhibition of miR-155 in the treatment of WM.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Yong
Y
Zhang
Aldo M
AM
Roccaro
Christopher
C
Rombaoa
Ludmilla
L
Flores
Susanna
S
Obad
Stacey M
SM
Fernandes
Antonio
A
Sacco
Yang
Y
Liu
Hai
H
Ngo
Phong
P
Quang
Abdel Kareem
AK
Azab
Feda
F
Azab
Patricia
P
Maiso
Michaela
M
Reagan
Jennifer R
JR
Brown
To-Ha
TH
Thai
Sakari
S
Kauppinen
Irene M
IM
Ghobrial
D000818:Animals; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D009841:Oligonucleotides / Q000235:genetics / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy
C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; C477371:locked nucleic acid