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. 2010 Aug 12;116(6):962-70.
doi: 10.1182/blood-2009-09-244673. Epub 2010 Jun 2.

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  1 , 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 Matsui, Toshiya Inaba, Kanji Sugita
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Free article

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 et al. Blood. .
Free article

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 RNA induced 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.

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