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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
2010-11-15
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pubmed:abstractText |
Core-binding factor leukemia (CBFL) is a subgroup of acute myeloid leukemia (AML) characterized by genetic mutations involving the subunits of the core-binding factor (CBF). The leukemogenesis model for CBFL posits that one, or more, gene mutations inducing increased cell proliferation and/or inhibition of apoptosis cooperate with CBF mutations for leukemia development. One of the most common mutations associated with CBF mutations involves the KIT receptor. A high expression of KIT is a hallmark of a high proportion of CBFL. Previous studies indicate that microRNA (MIR) 222/221 targets the 3' untranslated region of the KIT messenger RNA and our observation that AML1 can bind the MIR-222/221 promoter, we hypothesized that MIR-222/221 represents the link between CBF and KIT. Here, we show that MIR-222/221 expression is upregulated after myeloid differentiation of normal bone marrow AC133(+) stem progenitor cells. CBFL blasts with either t(8;21) or inv(16) CBF rearrangements with high expression levels of KIT (CD117) display a significantly lower level of MIR-222/221 expression than non-CBFL blasts. Consistently, we found that the t(8;21) AML1-MTG8 fusion protein binds the MIR-222/221 promoter and induces transcriptional repression of a MIR-222/221-LUC reporter. Because of the highly conserved sequence homology, we demonstrated concomitant MIR-222/221 down-regulation and KIT up-regulation in the 32D/WT1 mouse cell model carrying the AML1-MTG16 fusion protein. This study provides the first hint that CBFL-associated fusion proteins may lead to up-regulation of the KIT receptor by down-regulating MIR-222/221, thus explaining the concomitant occurrence of CBF genetic rearrangements and overexpression of wild type or mutant KIT in AML.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/AC133 antigen,
http://linkedlifedata.com/resource/pubmed/chemical/AML1-ETO fusion protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD,
http://linkedlifedata.com/resource/pubmed/chemical/Core Binding Factor Alpha 2 Subunit,
http://linkedlifedata.com/resource/pubmed/chemical/Core Binding Factor alpha Subunits,
http://linkedlifedata.com/resource/pubmed/chemical/Erythropoietin,
http://linkedlifedata.com/resource/pubmed/chemical/Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/MIRN221 microRNA, human,
http://linkedlifedata.com/resource/pubmed/chemical/MIRN222 microRNA, human,
http://linkedlifedata.com/resource/pubmed/chemical/MicroRNAs,
http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Proteins, Fusion,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-kit
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1476-5586
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pubmed:author |
pubmed-author:BeghiniAlessandroA,
pubmed-author:BrioschiMatteoM,
pubmed-author:CairoliRobertoR,
pubmed-author:CorlazzoliFrancescaF,
pubmed-author:FischerJohnJ,
pubmed-author:MorraEnricaE,
pubmed-author:NichelattiMicheleM,
pubmed-author:PezzettiLauraL,
pubmed-author:RossettiStefanoS,
pubmed-author:SacchiNicolettaN,
pubmed-author:ScarpatiBarbaraB,
pubmed-author:TurriniMauroM
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pubmed:issnType |
Electronic
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pubmed:volume |
12
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
866-76
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pubmed:meshHeading |
pubmed-meshheading:21076613-Acute Disease,
pubmed-meshheading:21076613-Adolescent,
pubmed-meshheading:21076613-Adult,
pubmed-meshheading:21076613-Aged,
pubmed-meshheading:21076613-Animals,
pubmed-meshheading:21076613-Antigens, CD,
pubmed-meshheading:21076613-Cell Differentiation,
pubmed-meshheading:21076613-Cell Line, Tumor,
pubmed-meshheading:21076613-Cells, Cultured,
pubmed-meshheading:21076613-Core Binding Factor Alpha 2 Subunit,
pubmed-meshheading:21076613-Core Binding Factor alpha Subunits,
pubmed-meshheading:21076613-Down-Regulation,
pubmed-meshheading:21076613-Erythropoietin,
pubmed-meshheading:21076613-Female,
pubmed-meshheading:21076613-Flow Cytometry,
pubmed-meshheading:21076613-Glycoproteins,
pubmed-meshheading:21076613-Hematopoietic Stem Cells,
pubmed-meshheading:21076613-Humans,
pubmed-meshheading:21076613-Leukemia, Myeloid,
pubmed-meshheading:21076613-Male,
pubmed-meshheading:21076613-MicroRNAs,
pubmed-meshheading:21076613-Middle Aged,
pubmed-meshheading:21076613-Mutation,
pubmed-meshheading:21076613-Oncogene Proteins, Fusion,
pubmed-meshheading:21076613-Peptides,
pubmed-meshheading:21076613-Proto-Oncogene Proteins c-kit,
pubmed-meshheading:21076613-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:21076613-U937 Cells
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pubmed:year |
2010
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pubmed:articleTitle |
Down-regulation of microRNAs 222/221 in acute myelogenous leukemia with deranged core-binding factor subunits.
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pubmed:affiliation |
Dipartimento di Biologia e Genetica per le Scienze Mediche, Facoltà di Medicina, Università degli Studi di Milano, Milan, Italy.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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