Two candidate downstream target genes for E2A-HLF.

Abstract

The E2A-HLF fusion gene, formed by the t(17;19)(q22;p13) chromosomal translocation, is thought to drive the leukemic transformation of early B-cell precursors by repressing an evolutionarily conserved apoptotic pathway. To test this hypothesis, we sought to identify downstream targets of E2A-HLF in t(17;19)+ pro-B leukemia cells (UOC-B1) that had been transfected with a zinc-inducible vector encoding a dominant-negative suppressor (E2A-HLF[dn]) of the oncoprotein. Representational difference analysis of mRNAs from E2A-HLF(dn)+ UOC-B1 cells grown with (E2A-HLF inactive) or without (E2A-HLF active) the addition of zinc yielded several differentially expressed cDNA fragments that were individually subcloned. Two of the clones, designated F-5 and G-4, hybridized with mRNAs that were upregulated by E2A-HLF. Levels of both transcripts declined sharply within 8 to 12 hours after suppression of E2A-HLF DNA-binding activity, becoming undetectable after 96 hours. The F-5 cDNA was identified as a portion of ANNEXIN VIII, whose product was expressed in promyelocytic leukemia cells and UOC-B1 cells, but not in other leukemic cell lines. A novel full-length cDNA cloned with the G-4 fragment encoded a protein that we have named SRPUL (sushi-repeat protein upregulated in leukemia). It is normally expressed in heart, ovary, and placenta, but could not be detected in leukemic cell lines other than UOC-B1. Neither protein prevented apoptosis in interleukin-3-dependent murine pro-B cells, suggesting that they have paraneoplastic roles in leukemias that express E2A-HLF, perhaps in the disseminated intravascular coagulopathy and hypercalcemia that characterize these cases.

• Authors: H Kurosawa, K Goi, T Inukai, T Inaba, K S Chang, T Shinjyo, K M Rakestraw, C W Naeve, A T Look
• Journal: Blood (Blood) Vol. 93 Issue 1 Pg. 321-32 (Jan 01 1999) ISSN: 0006-4971 [Print] United States
• PMID: 9864177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Annexins
• DNA-Binding Proteins
• E2a-Hlf fusion protein, human
• Membrane Proteins
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• SRPX2 protein, human
• Selectins
• Transcription Factors

Topics

• Amino Acid Sequence
• Annexins (genetics)
• Apoptosis
• Cell Line
• Cloning, Molecular
• DNA-Binding Proteins (genetics)
• Genes, Neoplasm
• Humans
• Membrane Proteins (biosynthesis, chemistry, genetics)
• Molecular Sequence Data
• Neoplasm Proteins
• Oncogene Proteins, Fusion (genetics)
• Repetitive Sequences, Amino Acid
• Selectins (chemistry, genetics)
• Transcription Factors (genetics)
• Tumor Cells, Cultured