Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19).
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.
Hirose
Kinuko
K
Department of Pediatrics, School of Medicine, University of Yamanashi, Shimokato, Yamanashi, Japan.
Inukai
Takeshi
T
Kikuchi
Jiro
J
Furukawa
Yusuke
Y
Ikawa
Tomokatsu
T
Kawamoto
Hiroshi
H
Oram
S Helen
SH
Göttgens
Berthold
B
Kiyokawa
Nobutaka
N
Miyagawa
Yoshitaka
Y
Okita
Hajime
H
Akahane
Koshi
K
Zhang
Xiaochun
X
Kuroda
Itaru
I
Honna
Hiroko
H
Kagami
Keiko
K
Goi
Kumiko
K
Kurosawa
Hidemitsu
H
Look
A Thomas
AT
Matsui
Hirotaka
H
Inaba
Toshiya
T
Sugita
Kanji
K
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002886:Chromosomes, Human, Pair 17; D002888:Chromosomes, Human, Pair 19; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D060588:LIM Domain Proteins; D016086:Lentivirus / Q000235:genetics; D008667:Metalloproteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic; D015854:Up-Regulation / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C076554:E2a-Hlf fusion protein, human; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors