UNIGE document Scientific Article
previous document  unige:55528  next document
add to browser collection
Title

Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2

Authors
Li, Feng-Qian
Person, Richard E
Takemaru, Ken-Ichi
Williams, Kayleen
Meade-White, Kimberly
Güngör, Tayfun
Moon, Randall T
show hidden authors show all authors [1 - 9]
Published in Journal of Biological Chemistry. 2004, vol. 279, no. 4, p. 2873-84
Abstract Two hereditary human leukemia syndromes are severe congenital neutropenia (SCN), caused by mutations in the gene ELA2, encoding the protease neutrophil elastase, and familial platelet disorder with acute myelogenous leukemia (AML), caused by mutations in the gene AML1, encoding the transcription factor core-binding factor alpha (CBFalpha). In mice, CBFalpha regulates the expression of ELA2, suggesting a common link for both diseases. However, gene-targeted mouse models have failed to reproduce either human disease, thus prohibiting further in vivo studies in mice. Here we investigate CBFalpha regulation of the human ELA2 promoter, taking advantage of bone marrow obtained from patients with either illness. In particular, we have identified novel ELA2 promoter substitutions (-199 C to A) within a potential motif for lymphoid enhancer factor-1 (LEF-1), a transcriptional mediator of Wnt/beta-catenin signaling, in SCN patients. The LEF-1 motif lies adjacent to a potential CBFalpha binding site that is in a different position in human compared with mouse ELA2. We find that LEF-1 and CBFalpha co-activate ELA2 expression. In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBFalpha. ELA2 transcript levels are up-regulated in bone marrow of an SCN patient with the -199 C to A substitution. Conversely, a mutation of the CBFalpha activation domain, found in a patient with familial platelet disorder with AML, fails to stimulate the ELA2 promoter in vitro, and bone marrow correspondingly demonstrates reduced ELA2 transcript. Observations in these complementary patients indicate that LEF-1 cooperates with CBFalpha to activate ELA2 in vivo and also suggest the possibility that up-regulating promoter mutations can contribute to SCN. Two hereditary AML predisposition syndromes may therefore intersect via LEF-1, potentially linking them to more generalized cancer mechanisms.
Keywords AnimalsBase SequenceCore Binding Factor alpha SubunitsDNA-Binding Proteins/genetics/metabolismEnhancer Elements, GeneticGene Expression Regulation, NeoplasticGenetic LinkageGenetic Predisposition to DiseaseHumansLeukemia/geneticsLeukocyte Elastase/genetics/metabolismLymphoid Enhancer-Binding Factor 1MiceMolecular Sequence DataMutationPromoter Regions, GeneticSyndromeTranscription Factors/genetics/metabolism
Identifiers
PMID: 14594802
Full text
Article (Published version) (3.6 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Citation
(ISO format)
LI, Feng-Qian et al. Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. In: Journal of Biological Chemistry, 2004, vol. 279, n° 4, p. 2873-84. https://archive-ouverte.unige.ch/unige:55528

177 hits

0 download

Update

Deposited on : 2015-04-14

Export document
Format :
Citation style :