Scientific article

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

Published inThe Journal of biological chemistry, vol. 279, no. 4, p. 2873-2884
Publication date2004

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.

  • Animals
  • Base Sequence
  • Core Binding Factor alpha Subunits
  • DNA-Binding Proteins/genetics/metabolism
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Humans
  • Leukemia/genetics
  • Leukocyte Elastase/genetics/metabolism
  • Lymphoid Enhancer-Binding Factor 1
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Promoter Regions, Genetic
  • Syndrome
  • Transcription Factors/genetics/metabolism
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: The Journal of biological chemistry, 2004, vol. 279, n° 4, p. 2873–2884. doi: 10.1074/jbc.M310759200
Main files (1)
Article (Published version)
ISSN of the journal0021-9258

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