Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19)

Kinuko Hirose, Takeshi Inukai, Jiro Kikuchi, Yusuke Furukawa, Tomokatsu Ikawa, Hiroshi Kawamoto, S. Helen Oram, Berthold Göttgens, Nobutaka Kiyokawa, Yoshitaka Miyagawa, Hajime Okita, Koshi Akahane, Xiaochun Zhang, Itaru Kuroda, Hiroko Honna, Keiko Kagami, Kumiko Goi, Hidemitsu Kurosawa, A. Thomas Look, Hirotaka MatsuiToshiya Inaba, Kanji Sugita

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

LMO2, a critical transcription regulator of hematopoiesis, is involved in human T-cell leukemia. The binding site of proline and acidic amino acid-rich protein (PAR) transcription factors in the promoter of the LMO2 gene plays a central role in hematopoietic-specific expression. E2A-HLF fusion derived from t(17;19) in B-precursor acute lymphoblastic leukemia (ALL) has the transactivation domain of E2A and the basic region/leucine zipper domain of HLF, which is a PAR transcription factor, raising the possibility that E2A-HLF aberrantly induces LMO2 expression. We here demonstrate that cell lines and a primary sample of t(17;19)-ALL expressed LMO2 at significantly higher levels than other B-precursor ALLs did. Transfection of E2A-HLF into a non-t(17;19) B-precursor ALL cell line induced LMO2 gene expression that was dependent on the DNA-binding and transactivation activities of E2A-HLF. The PAR site in the LMO2 gene promoter was critical for E2A-HLF-induced LMO2 expression. Gene silencing of LMO2 in a t(17;19)-ALL cell line by short hairpin RNAinduced apoptotic cell death. These observations indicated that E2A-HLF promotes cell survival of t(17;19)-ALL cells by aberrantly up-regulating LMO2 expression. LMO2 could be a target for a new therapeutic modality for extremely chemo-resistant t(17;19)-ALL.

Original languageEnglish
Pages (from-to)962-970
Number of pages9
JournalBlood
Volume116
Issue number6
DOIs
Publication statusPublished - 2010 Aug 12
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Hirose, K., Inukai, T., Kikuchi, J., Furukawa, Y., Ikawa, T., Kawamoto, H., Oram, S. H., Göttgens, B., Kiyokawa, N., Miyagawa, Y., Okita, H., Akahane, K., Zhang, X., Kuroda, I., Honna, H., Kagami, K., Goi, K., Kurosawa, H., Look, A. T., ... Sugita, K. (2010). Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19). Blood, 116(6), 962-970. https://doi.org/10.1182/blood-2009-09-244673