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

• Published in: Blood Vol. 116; no. 6; pp. 962 - 970
• Main Authors: Hirose, Kinuko, Inukai, Takeshi, Kikuchi, Jiro, Furukawa, Yusuke, Ikawa, Tomokatsu, Kawamoto, Hiroshi, Oram, S. Helen, Göttgens, 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.08.2010
• Subjects: Adaptor Proteins, Signal Transducing; Apoptosis - physiology; Blotting, Western; Cell Line, Tumor; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 19; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fetal Blood - cytology; Gene Expression Regulation, Leukemic; Humans; Lentivirus - genetics; LIM Domain Proteins; Metalloproteins - genetics; Metalloproteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cells, B-Lymphoid - cytology; Precursor Cells, B-Lymphoid - physiology; Promoter Regions, Genetic - physiology; Proto-Oncogene Proteins; RNA, Small Interfering; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation, Genetic; Up-Regulation - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• 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.