Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice.
We showed that Emicro-MiR-155 transgenic mice develop acute lymphoblastic leukemia/high-grade lymphoma. Most of these leukemias start at approximately 9 months irrespective of the mouse strain. They are preceded by a polyclonal pre-B-cell proliferation, have variable clinical presentation, are transplantable, and develop oligo/monoclonal expansion. In this study, we show that in these transgenic mice the B-cell precursors have the highest MiR-155 transgene expression and are at the origin of the leukemias. We determine that Src homology 2 domain-containing inositol-5-phosphatase (SHIP) and CCAAT enhancer-binding protein beta (C/EBPbeta), 2 important regulators of the interleukin-6 signaling pathway, are direct targets of MiR-155 and become gradually more down-regulated in the leukemic than in the preleukemic mice. We hypothesize that miR-155, by down-modulating Ship and C/EBPbeta, initiates a chain of events that leads to the accumulation of large pre-B cells and acute lymphoblastic leukemia/high-grade lymphoma.
Costinean
Stefan
S
Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Sandhu
Sukhinder K
SK
Pedersen
Irene M
IM
Tili
Esmerina
E
Trotta
Rossana
R
Perrotti
Danilo
D
Ciarlariello
David
D
Neviani
Paolo
P
Harb
Jason
J
Kauffman
Lauren Rachel
LR
Shidham
Aaditya
A
Croce
Carlo Maria
CM
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis* / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D000072181:Inositol Polyphosphate 5-Phosphatases; D015850:Interleukin-6 / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; D015850:Interleukin-6; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases