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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 321-332
Two Candidate Downstream Target Genes for E2A-HLF
Hidemitsu Kurosawa,
Kumiko Goi,
Takeshi Inukai,
Toshiya Inaba,
Kun-San Chang,
Tetsuharu Shinjyo,
Karen M. Rakestraw,
Clayton W. Naeve, and
A. Thomas Look
From the Department of Experimental Oncology and the Center for
Biotechnology, St Jude Children's Research Hospital, Memphis, TN; the
Department of Pediatrics, University of Tennessee College of Medicine,
Memphis, TN; Jichi Medical School, Tochigi, Japan; and the Division of
Laboratory Medicine, the University of Texas M.D. Anderson Cancer
Center, Houston, TX.
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.
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