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

Number of Access:3,737（2025-07-18 19:15 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/97607

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Title	Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia
Creator	NRID 1000080825779 1000080825779 ORCID 0000-0002-2092-8194 0000-0002-2092-8194 researchmap permalink ryoyanagiya ryoyanagiya CreatorName Yanagiya, Ryo
	NRID 1000030868881 1000030868881 ORCID 0000-0002-6748-608X 0000-0002-6748-608X researchmap permalink mytk mytk CreatorName Miyatake, Yuji
	CreatorName Watanabe, Natsumi
	CreatorName Shimizu, Takanobu
	CreatorName Kanamori, Akane
	CreatorName Ueno, Masaya
	CreatorName Okabe, Sachiko
	NRID 1000090637191 1000090637191 CreatorName Carreras, Joaquim
	NRID 1000070884196 1000070884196 CreatorName Nakayama, Shunya
	CreatorName Hasegawa, Ami
	CreatorName Kameda, Kazuaki
	NRID 1000030600564 1000030600564 researchmap permalink t_kamakura3519 t_kamakura3519 CreatorName Kamakura, Takeshi
	NRID 1000070510014 1000070510014 CreatorName Nakagawa, So
	NRID 1000020796213 1000020796213 CreatorName Yamauchi, Takuji
	NRID 1000000791972 1000000791972 CreatorName Maeda, Takahiro
	CreatorName Ishii, Keisuke
	CreatorName Matsuura, Tadashi
	NRID 1000090282409 1000090282409 CreatorName Handa, Hiroshi
	NRID 1000090343350 1000090343350 CreatorName Hirao, Atsushi
	NRID 1000000359506 1000000359506 CreatorName Ishizawa, Kenichi
	NRID 1000080366012 1000080366012 CreatorName Onizuka, Makoto
	NRID 1000030311228 1000030311228 CreatorName Mashima, Tetsuo
	NRID 1000050227922 1000050227922 CreatorName Nakamura, Naoya
	NRID 1000070176014 1000070176014 CreatorName Ando, Kiyoshi
	NRID 1000000517477 1000000517477 ORCID 0000-0002-0976-8687 0000-0002-0976-8687 researchmap permalink aikotani aikotani CreatorName Kotani, Ai
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.
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.)
Publisher	Springer Nature
Source Title	Leukemia
Volume (Issue)	38(8)
Page	1731-1741
Date of Issued	2024-06-24
Language	English
Handle URL	https://hdl.handle.net/11094/97607
PISSN	08876924
eISSN	14765551
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1038/s41375-024-02296-6
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
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	English
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	English
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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