Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Takeshi Ueda; Akiko Nagamachi; Keiyo Takubo; Norimasa Yamasaki; Hirotaka Matsui; Akinori Kanai; Yuichiro Nakata; Kenichiro Ikeda; Takaaki Konuma; Hideaki Oda; Linda Wolff; Zen-Ichiro Honda; Xudong Wu; Kristian Helin; Atsushi Iwama; Toshio Suda; Toshiya Inaba; Hiroaki Honda

doi:10.1182/blood-2014-03-562694

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Takeshi Ueda, Akiko Nagamachi, Keiyo Takubo, Norimasa Yamasaki, Hirotaka Matsui, Akinori Kanai, Yuichiro Nakata, Kenichiro Ikeda, Takaaki Konuma, Hideaki Oda, Linda Wolff, Zen-Ichiro Honda, Xudong Wu, Kristian Helin, Atsushi Iwama, Toshio Suda, Toshiya Inaba, Hiroaki Honda

41 Citations (Scopus)

Abstract

Wepreviously reported that deficiency forSamd9L, whichwascloned as a candidate gene for-7/7q-syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fb×l10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fb×l10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fb×l10 in hematopoietic stem cells (HSCs). Interestingly, Fb×l10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fb×l10TgHSCsdisplayed enhancedexpression of neuron-specific gene familymember2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fb×l10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fb×l10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fb×l10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446).

Original language	English
Journal	Blood
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2014-03-562694
Publication status	Published - 28 May 2015

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Ueda, T., Nagamachi, A., Takubo, K., Yamasaki, N., Matsui, H., Kanai, A., Nakata, Y., Ikeda, K., Konuma, T., Oda, H., Wolff, L., Honda, Z-I., Wu, X., Helin, K., Iwama, A., Suda, T., Inaba, T., & Honda, H. (2015). Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2. Blood. https://doi.org/10.1182/blood-2014-03-562694

Ueda, T, Nagamachi, A, Takubo, K, Yamasaki, N, Matsui, H, Kanai, A, Nakata, Y, Ikeda, K, Konuma, T, Oda, H, Wolff, L, Honda, Z-I, Wu, X, Helin, K, Iwama, A, Suda, T, Inaba, T & Honda, H 2015, 'Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2', Blood. https://doi.org/10.1182/blood-2014-03-562694

@article{c5a9907377a8423c84544956bf684693,

title = "Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2",

abstract = "Wepreviously reported that deficiency forSamd9L, whichwascloned as a candidate gene for-7/7q-syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fb×l10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fb×l10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fb×l10 in hematopoietic stem cells (HSCs). Interestingly, Fb×l10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fb×l10TgHSCsdisplayed enhancedexpression of neuron-specific gene familymember2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fb×l10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fb×l10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fb×l10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446).",

author = "Takeshi Ueda and Akiko Nagamachi and Keiyo Takubo and Norimasa Yamasaki and Hirotaka Matsui and Akinori Kanai and Yuichiro Nakata and Kenichiro Ikeda and Takaaki Konuma and Hideaki Oda and Linda Wolff and Zen-Ichiro Honda and Xudong Wu and Kristian Helin and Atsushi Iwama and Toshio Suda and Toshiya Inaba and Hiroaki Honda",

note = "Copyright {\textcopyright} 2015 American Society of Hematology.",

year = "2015",

month = may,

day = "28",

doi = "10.1182/blood-2014-03-562694",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

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TY - JOUR

T1 - Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

AU - Ueda, Takeshi

AU - Nagamachi, Akiko

AU - Takubo, Keiyo

AU - Yamasaki, Norimasa

AU - Matsui, Hirotaka

AU - Kanai, Akinori

AU - Nakata, Yuichiro

AU - Ikeda, Kenichiro

AU - Konuma, Takaaki

AU - Oda, Hideaki

AU - Wolff, Linda

AU - Honda, Zen-Ichiro

AU - Wu, Xudong

AU - Helin, Kristian

AU - Iwama, Atsushi

AU - Suda, Toshio

AU - Inaba, Toshiya

AU - Honda, Hiroaki

PY - 2015/5/28

Y1 - 2015/5/28

N2 - Wepreviously reported that deficiency forSamd9L, whichwascloned as a candidate gene for-7/7q-syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fb×l10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fb×l10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fb×l10 in hematopoietic stem cells (HSCs). Interestingly, Fb×l10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fb×l10TgHSCsdisplayed enhancedexpression of neuron-specific gene familymember2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fb×l10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fb×l10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fb×l10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446).

AB - Wepreviously reported that deficiency forSamd9L, whichwascloned as a candidate gene for-7/7q-syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fb×l10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fb×l10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fb×l10 in hematopoietic stem cells (HSCs). Interestingly, Fb×l10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fb×l10TgHSCsdisplayed enhancedexpression of neuron-specific gene familymember2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fb×l10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fb×l10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fb×l10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446).

U2 - 10.1182/blood-2014-03-562694

DO - 10.1182/blood-2014-03-562694

M3 - Journal article

C2 - 25872778

SN - 0006-4971

JO - Blood

JF - Blood

ER -

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

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