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

作者：Hirose Kinuko; Inukai Takeshi^*; Kikuchi Jiro; Furukawa Yusuke; Ikawa Tomokatsu; Kawamoto Hiroshi; Oram S Helen; Goettgens Berthold; Kiyokawa Nobutaka; Miyagawa Yoshitaka; Okita Hajime; Akahane Koshi; Zhang Xiaochun; Kuroda Itaru; Honna Hiroko; Kagami Keiko; Goi Kumiko; Kurosawa Hidemitsu; Look A Thomas; Matsui Hirotaka; Inaba Toshiya; Sugita Kanji

来源：Blood, 2010, 116(6): 962-970.

DOI：10.1182/blood-2009-09-244673

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. (Blood. 2010;116(6):962-970)

• 出版日期2010-8-12
• 单位河北医科大学