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

Author:

Yanagiya RyoORCID,Miyatake Yuji,Watanabe Natsumi,Shimizu Takanobu,Kanamori Akane,Ueno MasayaORCID,Okabe Sachiko,Carreras JoaquimORCID,Nakayama Shunya,Hasegawa Ami,Kameda Kazuaki,Kamakura Takeshi,Nakagawa So,Yamauchi Takuji,Maeda TakahiroORCID,Ishii Keisuke,Matsuura Tadashi,Handa HiroshiORCID,Hirao AtsushiORCID,Ishizawa Kenichi,Onizuka Makoto,Mashima Tetsuo,Nakamura Naoya,Ando Kiyoshi,Kotani AiORCID

Abstract

AbstractAggressive 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.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

MEXT | Japan Science and Technology Agency

Tokai University Tokuda Memorial Cancer/Genome Basic Research Grant for Young Investigators

Publisher

Springer Science and Business Media LLC

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