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.
Down-regulation of microRNAs 222/221 in acute myelogenous leukemia with deranged core-binding factor subunits / M. Brioschi, J. Fischer, R. Cairoli, S. Rossetti, L. Pezzetti, M. Nichelatti, M. Turrini, F. Corlazzoli, B. Scarpati, E. Morra, N. Sacchi, A. Beghini. - In: NEOPLASIA. - ISSN 1522-8002. - 12:11(2010 Nov), pp. 866-876.
|Titolo:||Down-regulation of microRNAs 222/221 in acute myelogenous leukemia with deranged core-binding factor subunits|
SACCHI, NICOLETTA (Penultimo)
BEGHINI, ALESSANDRO (Ultimo)
|Parole Chiave:||MicroRNA; KIT; AML; Core Binding Factor, MIR-221; MIR-222|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
Settore BIO/11 - Biologia Molecolare
|Data di pubblicazione:||nov-2010|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1593/neo.10482|
|Appare nelle tipologie:||01 - Articolo su periodico|