Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia

Yanagiya, Ryo; Miyatake, Yuji; Watanabe, Natsumi; Shimizu, Takanobu; Kanamori, Akane; Ueno, Masaya; Okabe, Sachiko; Carreras, Joaquim; Nakayama, Shunya; Hasegawa, Ami; Kameda, Kazuaki; Kamakura, Takeshi; Nakagawa, So; Yamauchi, Takuji; Maeda, Takahiro; Ishii, Keisuke; Matsuura, Tadashi; Handa, Hiroshi; Hirao, Atsushi; Ishizawa, Kenichi; Onizuka, Makoto; Mashima, Tetsuo; Nakamura, Naoya; Ando, Kiyoshi; Kotani, Ai

doi:https://doi.org/10.1038/s41375-024-02296-6

Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia

Yanagiya, Ryo; Miyatake, Yuji; Watanabe, Natsumi et al.

Leukemia, 2024, 38(8), 1731-1741

アクセス数:2,878件（2025-07-02 00:42 集計）

固定URL: https://hdl.handle.net/11094/97607

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タイトル	Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia
著者	NRID 1000080825779 1000080825779 ORCID 0000-0002-2092-8194 0000-0002-2092-8194 researchmap permalink ryoyanagiya ryoyanagiya 著者名 Yanagiya, Ryo
	NRID 1000030868881 1000030868881 ORCID 0000-0002-6748-608X 0000-0002-6748-608X researchmap permalink mytk mytk 著者名 Miyatake, Yuji
	著者名 Watanabe, Natsumi
	著者名 Shimizu, Takanobu
	著者名 Kanamori, Akane
	著者名 Ueno, Masaya
	著者名 Okabe, Sachiko
	NRID 1000090637191 1000090637191 著者名 Carreras, Joaquim
	NRID 1000070884196 1000070884196 著者名 Nakayama, Shunya
	著者名 Hasegawa, Ami
	著者名 Kameda, Kazuaki
	NRID 1000030600564 1000030600564 researchmap permalink t_kamakura3519 t_kamakura3519 著者名 Kamakura, Takeshi
	NRID 1000070510014 1000070510014 著者名 Nakagawa, So
	NRID 1000020796213 1000020796213 著者名 Yamauchi, Takuji
	NRID 1000000791972 1000000791972 著者名 Maeda, Takahiro
	著者名 Ishii, Keisuke
	著者名 Matsuura, Tadashi
	NRID 1000090282409 1000090282409 著者名 Handa, Hiroshi
	NRID 1000090343350 1000090343350 著者名 Hirao, Atsushi
	NRID 1000000359506 1000000359506 著者名 Ishizawa, Kenichi
	NRID 1000080366012 1000080366012 著者名 Onizuka, Makoto
	NRID 1000030311228 1000030311228 著者名 Mashima, Tetsuo
	NRID 1000050227922 1000050227922 著者名 Nakamura, Naoya
	NRID 1000070176014 1000070176014 著者名 Ando, Kiyoshi
	NRID 1000000517477 1000000517477 ORCID 0000-0002-0976-8687 0000-0002-0976-8687 researchmap permalink aikotani aikotani 著者名 Kotani, Ai
内容	Yanagiya R., Miyatake Y., Watanabe N., et al. Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia. Leukemia , (2024); 10.1038/s41375-024-02296-6.
抄録	Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy with a fulminant clinical course. Our previous study revealed that ANKL cells proliferate predominantly in the liver sinusoids and strongly depend on transferrin supplementation. In addition, we demonstrated that liver-resident ANKL cells are sensitive to PPMX-T003, an anti-human transferrin receptor 1 inhibitory antibody, whereas spleen-resident ANKL cells are resistant to transferrin receptor 1 inhibition. However, the microenvironmental factors that regulate the iron dependency of ANKL cells remain unclear. In this study, we first revealed that the anti-neoplastic effect of PPMX-T003 was characterized by DNA double-strand breaks in a DNA replication-dependent manner, similar to conventional cytotoxic agents. We also found that the influx of extracellular amino acids via LAT1 stimulated sensitivity to PPMX-T003. Taken together, we discovered that the amount of extracellular amino acid influx through LAT1 was the key environmental factor determining the iron dependency of ANKL cells via adjustment of their mTOR/Myc activity, which provides a good explanation for the different sensitivity to PPMX-T003 between liver- and spleen-resident ANKL cells, as the liver sinusoid contains abundant amino acids absorbed from the gut. (Figure presented.)
出版者	Springer Nature
収録物名	Leukemia
巻(号)	38(8)
ページ	1731-1741
刊行年月	2024-06-24
言語	英語
ハンドルURL	https://hdl.handle.net/11094/97607
PISSN	08876924
eISSN	14765551
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1038/s41375-024-02296-6
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	Leukemia. 2024, 38(8), p. 1731-1741
DC.title	Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia
DC.creator	Yanagiya, Ryo
	Miyatake, Yuji
	Watanabe, Natsumi
	Shimizu, Takanobu
	Kanamori, Akane
	Ueno, Masaya
	Okabe, Sachiko
	Carreras, Joaquim
	Nakayama, Shunya
	Hasegawa, Ami
	Kameda, Kazuaki
	Kamakura, Takeshi
	Nakagawa, So
	Yamauchi, Takuji
	Maeda, Takahiro
	Ishii, Keisuke
	Matsuura, Tadashi
	Handa, Hiroshi
	Hirao, Atsushi
	Ishizawa, Kenichi
	Onizuka, Makoto
	Mashima, Tetsuo
	Nakamura, Naoya
	Ando, Kiyoshi
	Kotani, Ai
DC.publisher	Springer Nature
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-06-24
DC.identifier	https://doi.org/10.1038/s41375-024-02296-6
DC.description	Yanagiya R., Miyatake Y., Watanabe N., et al. Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia. Leukemia , (2024); 10.1038/s41375-024-02296-6.
DCTERMS.abstract	Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy with a fulminant clinical course. Our previous study revealed that ANKL cells proliferate predominantly in the liver sinusoids and strongly depend on transferrin supplementation. In addition, we demonstrated that liver-resident ANKL cells are sensitive to PPMX-T003, an anti-human transferrin receptor 1 inhibitory antibody, whereas spleen-resident ANKL cells are resistant to transferrin receptor 1 inhibition. However, the microenvironmental factors that regulate the iron dependency of ANKL cells remain unclear. In this study, we first revealed that the anti-neoplastic effect of PPMX-T003 was characterized by DNA double-strand breaks in a DNA replication-dependent manner, similar to conventional cytotoxic agents. We also found that the influx of extracellular amino acids via LAT1 stimulated sensitivity to PPMX-T003. Taken together, we discovered that the amount of extracellular amino acid influx through LAT1 was the key environmental factor determining the iron dependency of ANKL cells via adjustment of their mTOR/Myc activity, which provides a good explanation for the different sensitivity to PPMX-T003 between liver- and spleen-resident ANKL cells, as the liver sinusoid contains abundant amino acids absorbed from the gut. (Figure presented.)
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	97607
citation_title	Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia
citation_author	Yanagiya, Ryo
	Miyatake, Yuji
	Watanabe, Natsumi
	Shimizu, Takanobu
	Kanamori, Akane
	Ueno, Masaya
	Okabe, Sachiko
	Carreras, Joaquim
	Nakayama, Shunya
	Hasegawa, Ami
	Kameda, Kazuaki
	Kamakura, Takeshi
	Nakagawa, So
	Yamauchi, Takuji
	Maeda, Takahiro
	Ishii, Keisuke
	Matsuura, Tadashi
	Handa, Hiroshi
	Hirao, Atsushi
	Ishizawa, Kenichi
	Onizuka, Makoto
	Mashima, Tetsuo
	Nakamura, Naoya
	Ando, Kiyoshi
	Kotani, Ai
citation_publisher	Springer Nature
citation_language	英語
citation_date	2024-06-24
citation_journal_title	Leukemia
citation_volume	38
citation_issue	8
citation_firstpage	1731
citation_lastpage	1741
citation_doi	https://doi.org/10.1038/s41375-024-02296-6
citation_public_url	https://hdl.handle.net/11094/97607

Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia

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