Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor.
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.
Inaba
T
T
Department of Experimental Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Inukai
T
T
Yoshihara
T
T
Seyschab
H
H
Ashmun
R A
RA
Canman
C E
CE
Laken
S J
SJ
Kastan
M B
MB
Look
A T
AT
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D001402:B-Lymphocytes / Q000166:cytology; D050976:Basic-Leucine Zipper Transcription Factors; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002886:Chromosomes, Human, Pair 17; D002888:Chromosomes, Human, Pair 19; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000037:antagonists & inhibitors; D016350:Leucine Zippers; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D015032:Zinc / Q000502:physiology
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C076554:E2a-Hlf fusion protein, human; C489626:E2a-Hlf fusion protein, mouse; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004247:DNA; D015032:Zinc