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; 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

doi:10.1182/blood-2009-09-244673

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, 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 MatsuiToshiya Inaba, Kanji Sugita

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

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 RNAinduced 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.

Original language	English
Pages (from-to)	962-970
Number of pages	9
Journal	Blood
Volume	116
Issue number	6
DOIs	https://doi.org/10.1182/blood-2009-09-244673
Publication status	Published - 2010 Aug 12
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Hirose, K., Inukai, T., Kikuchi, J., Furukawa, Y., Ikawa, T., Kawamoto, H., Oram, S. H., Göttgens, B., Kiyokawa, N., Miyagawa, Y., Okita, H., Akahane, K., Zhang, X., Kuroda, I., Honna, H., Kagami, K., Goi, K., Kurosawa, H., Look, A. T., ... Sugita, K. (2010). Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19). Blood, 116(6), 962-970. https://doi.org/10.1182/blood-2009-09-244673

Hirose, K, Inukai, T, Kikuchi, J, Furukawa, Y, Ikawa, T, Kawamoto, H, Oram, SH, Göttgens, B, Kiyokawa, N, Miyagawa, Y, Okita, H, Akahane, K, Zhang, X, Kuroda, I, Honna, H, Kagami, K, Goi, K, Kurosawa, H, Look, AT, Matsui, H, Inaba, T & Sugita, K 2010, 'Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19)', Blood, vol. 116, no. 6, pp. 962-970. https://doi.org/10.1182/blood-2009-09-244673

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

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 RNAinduced 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.",

author = "Kinuko Hirose and Takeshi Inukai and Jiro Kikuchi and Yusuke Furukawa and Tomokatsu Ikawa and Hiroshi Kawamoto and Oram, {S. Helen} and Berthold G{\"o}ttgens and Nobutaka Kiyokawa and Yoshitaka Miyagawa and Hajime Okita and Koshi Akahane and Xiaochun Zhang and Itaru Kuroda and Hiroko Honna and Keiko Kagami and Kumiko Goi and Hidemitsu Kurosawa and Look, {A. Thomas} and Hirotaka Matsui and Toshiya Inaba and Kanji Sugita",

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doi = "10.1182/blood-2009-09-244673",

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T1 - Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19)

AU - Hirose, Kinuko

AU - Inukai, Takeshi

AU - Kikuchi, Jiro

AU - Furukawa, Yusuke

AU - Ikawa, Tomokatsu

AU - Kawamoto, Hiroshi

AU - Oram, S. Helen

AU - Göttgens, Berthold

AU - Kiyokawa, Nobutaka

AU - Miyagawa, Yoshitaka

AU - Okita, Hajime

AU - Akahane, Koshi

AU - Zhang, Xiaochun

AU - Kuroda, Itaru

AU - Honna, Hiroko

AU - Kagami, Keiko

AU - Goi, Kumiko

AU - Kurosawa, Hidemitsu

AU - Look, A. Thomas

AU - Matsui, Hirotaka

AU - Inaba, Toshiya

AU - Sugita, Kanji

PY - 2010/8/12

Y1 - 2010/8/12

N2 - 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 RNAinduced 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.

AB - 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 RNAinduced 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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SN - 0006-4971

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JO - Blood

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

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