Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma.
LIN28A and LIN28B, the mammalian homologs of lin-28, are implicated in malignant transformation in part because of their ability to promote degradation of the let-7 family of miRs. In the present study, we show that overexpression of Lin28b in vivo leads to an aggressive peripheral T-cell lymphoma (PTCL) characterized by widespread infiltration of parenchymal organs with malignant CD4(+) cells. Similar to patients with PTCL, Lin28b-transgenic mice show signs of inflammation such as eosinophilia, increased C-reactive protein, release of inflammatory cytokines, and pleural effusion. The PTCLs that develop in Lin28b mice are derived from activated T cells and show decreased let-7 expression, increased Il6 expression, activation of NF-κB, and infiltration of B cells, all resulting in an inflammatory microenvironment. In addition, LIN28B is overexpressed 7.5-fold in PTCL patient samples compared with activated CD4(+) cells. The results of the present study demonstrate for the first time that Lin28b can transform primary cells in vivo, identify a previously unsuspected link between Lin28b and PTCL, and provide a unique animal model for the study of PTCL biology and therapy.
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sarah H
SH
Beachy
Masahiro
M
Onozawa
Yang Jo
YJ
Chung
Chris
C
Slape
Sven
S
Bilke
Princy
P
Francis
Marbin
M
Pineda
Robert L
RL
Walker
Paul
P
Meltzer
Peter D
PD
Aplan
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016601:RNA-Binding Proteins; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; C570876:Lin28b protein, mouse; D016601:RNA-Binding Proteins