Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor

T Inaba; T Inukai; T Yoshihara; H Seyschab; R A Ashmun; C E Canman; S J Laken; M B Kastan; A T Look

doi:10.1038/382541a0

Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor

Nature. 1996 Aug 8;382(6591):541-4. doi: 10.1038/382541a0.

Authors

T Inaba¹, T Inukai, T Yoshihara, H Seyschab, R A Ashmun, C E Canman, S J Laken, M B Kastan, A T Look

Affiliation

¹ Department of Experimental Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

PMID: 8700228
DOI: 10.1038/382541a0

Abstract

The E2A-HLF (for hepatic leukaemia factor) fusion gene, formed by action of the t(17;19) (q22;p13) chromosomal translocation, drives the leukaemic transformation of early B-cell precursors, but the mechanism of this activity remains unknown. Here we report that human leukaemia cells carrying the translocation t(17;19) rapidly died by apoptosis when programmed to express a dominant-negative suppressor of the fusion protein E2A-HLF, indicating that the chimaeric oncoprotein probably affects cell survival rather than cell growth. Moreover, when introduced into murine pro-B lymphocytes, the oncogenic E2A-HLF fusion protein reversed both interleukin-3-dependent and p53-mediated apoptosis. The close homology of the basic region/leucine zipper (bZIP) DNA-binding and dimerization domain of HLF to that of the CES-2 cell-death specification protein of Caenorhabditis elegans suggests a model of leukaemogenesis in which E2A-HLF blocks an early step within an evolutionarily conserved cell-death pathway.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acid Sequence
Animals
Apoptosis / physiology*
Apoptosis / radiation effects
B-Lymphocytes / cytology
Basic-Leucine Zipper Transcription Factors
Cell Cycle / physiology
Cell Division / physiology
Cell Line
Chromosomes, Human, Pair 17
Chromosomes, Human, Pair 19
DNA / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology*
Humans
Interleukin-3 / antagonists & inhibitors
Leucine Zippers
Mice
Molecular Sequence Data
Mutation
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / physiology*
Transcription Factors / genetics
Transcription Factors / physiology*
Translocation, Genetic
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / antagonists & inhibitors
Zinc / physiology

Substances

Basic-Leucine Zipper Transcription Factors
DNA-Binding Proteins
E2a-Hlf fusion protein, human
E2a-Hlf fusion protein, mouse
Interleukin-3
Oncogene Proteins, Fusion
Transcription Factors
Tumor Suppressor Protein p53
DNA
Zinc