The E2A-HLF oncogenic fusion protein acts through Lmo2 and Bcl-2 to immortalize hematopoietic progenitors.
The oncogenic fusion protein E2A-HLF is a chimeric transcription factor that arises from the t(17;19) translocation in childhood B-cell acute lymphoblastic leukemias (B-precursor ALL) and is associated with very poor outcome. We show that retroviral-mediated expression of E2A-HLF alone is sufficient to immortalize primary lymphoid progenitors. We identify Lmo2 and Bcl-2 as direct target genes downstream of E2A-HLF. We use real-time PCR analysis to show that LMO2 and BCL-2 expression is preferentially upregulated both in biopsy material from t(17;19) B-precursor ALL patients and lymphoid cell lines derived from t(17;19) leukemias. Co-expression of Lmo2 and Bcl-2 was sufficient to immortalize lymphoid progenitor cells resulting in a similar phenotype to that induced by E2A-HLF alone. Both shRNA-mediated knockdown of Lmo2 expression and pharmacological inhibition of BCL-2 function in E2A-HLF immortalized cells severely compromised their viability. These data suggest that both Lmo2 and Bcl-2 are required for the action of E2A-HLF in leukemogenesis.
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, UK.
J
J
de Boer
J
J
Yeung
J
J
Ellu
R
R
Ramanujachar
B
B
Bornhauser
O
O
Solarska
M
M
Hubank
O
O
Williams
H J M
HJ
Brady
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D060588:LIM Domain Proteins; D007938:Leukemia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008667:Metalloproteins / Q000235:genetics*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012190:Retroviridae; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C076554:E2a-Hlf fusion protein, human; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors