Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes.
The genomic region encoding the miR-17-92 microRNA (miRNA) cluster is often amplified in lymphoma and other cancers, and cancer cells carrying this amplification have higher expression of miRNA in this cluster. Retroviral expression of miR-17-92 accelerates c-Myc-induced lymphoma development, but precisely how higher expression of miR-17-92 promotes lymphomagenesis remains unclear. Here we generated mice with higher expression of miR-17-92 in lymphocytes. These mice developed lymphoproliferative disease and autoimmunity and died prematurely. Lymphocytes from these mice showed more proliferation and less activation-induced cell death. The miR-17-92 miRNA suppressed expression of the tumor suppressor PTEN and the proapoptotic protein Bim. This mechanism probably contributed to the lymphoproliferative disease and autoimmunity of miR-17-92-transgenic mice and contributes to lymphoma development in patients with amplifications of the miR-17-92 coding region.
Xiao
Changchun
C
Immune Disease Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Srinivasan
Lakshmi
L
Calado
Dinis Pedro
DP
Patterson
Heide Christine
HC
Zhang
Baochun
B
Wang
Jing
J
Henderson
Joel M
JM
Kutok
Jeffrey L
JL
Rajewsky
Klaus
K
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
C524941:MIRN17 microRNA, human; D035683:MicroRNAs