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

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:2010-08-12 Issue:6 Volume:116 Page:962-970
ISSN:0006-4971
Container-title:Blood
language:en
Short-container-title:

Author:

Hirose Kinuko¹,Inukai Takeshi¹,Kikuchi Jiro²,Furukawa Yusuke²,Ikawa Tomokatsu³,Kawamoto Hiroshi³,Oram S. Helen⁴,Göttgens Berthold⁴,Kiyokawa Nobutaka⁵,Miyagawa Yoshitaka⁵,Okita Hajime⁵,Akahane Koshi¹,Zhang Xiaochun¹,Kuroda Itaru¹,Honna Hiroko¹,Kagami Keiko¹,Goi Kumiko¹,Kurosawa Hidemitsu⁶,Look A. Thomas⁷,Matsui Hirotaka⁸,Inaba Toshiya⁸,Sugita Kanji¹

Affiliation:

1. Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan;

2. Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan;

3. Laboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan;

4. Department of Haematology, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom;

5. Developmental Biology, National Research Institute for Child Health and Development, Tokyo, Japan;

6. Department of Pediatrics, Dokkyo Medical School, Tochigi, Japan;

7. Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; and

8. Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Link

http://ashpublications.org/blood/article-pdf/116/6/962/1460441/zh803210000962.pdf

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