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1. Hyperactive Natural Killer cells in Rag2 knockout mice inhibit the development of acute myeloid leukemia

Author

Sugimoto, Emi, Li, Jingmei, Hayashi, Yasutaka, Iida, Kohei, Asada, Shuhei, Fukushima, Tsuyoshi, Tamura, Moe, Shikata, Shiori, Zhang, Wenyu, Yamamoto, Keita, Kawabata, Kimihito Cojin, Kawase, Tatsuya, Saito, Takeshi, Yoshida, Taku, Yamazaki, Satoshi, Kaito, Yuta, Imai, Yoichi, Denda, Tamami, Ota, Yasunori, Fukuyama, Tomofusa, Tanaka, Yosuke, Enomoto, Yutaka, Kitamura, Toshio, and Goyama, Susumu

Published
2023
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3. MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis

Author

Hayashi, Yasutaka, Kawabata, Kimihito C., Tanaka, Yosuke, Uehara, Yasufumi, Mabuchi, Yo, Murakami, Koichi, Nishiyama, Akira, Kiryu, Shigeru, Yoshioka, Yusuke, Ota, Yasunori, Sugiyama, Tatsuki, Mikami, Keiko, Tamura, Moe, Fukushima, Tsuyoshi, Asada, Shuhei, Takeda, Reina, Kunisaki, Yuya, Fukuyama, Tomofusa, Yokoyama, Kazuaki, Uchida, Tomoyuki, Hagihara, Masao, Ohno, Nobuhiro, Usuki, Kensuke, Tojo, Arinobu, Katayama, Yoshio, Goyama, Susumu, Arai, Fumio, Tamura, Tomohiko, Nagasawa, Takashi, Ochiya, Takahiro, Inoue, Daichi, and Kitamura, Toshio

Published
2022
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4. Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

Author

Isobe, Tomoya, Takagi, Masatoshi, Sato-Otsubo, Aiko, Nishimura, Akira, Nagae, Genta, Yamagishi, Chika, Tamura, Moe, Tanaka, Yosuke, Asada, Shuhei, Takeda, Reina, Tsuchiya, Akiho, Wang, Xiaonan, Yoshida, Kenichi, Nannya, Yasuhito, Ueno, Hiroo, Akazawa, Ryo, Kato, Itaru, Mikami, Takashi, Watanabe, Kentaro, Sekiguchi, Masahiro, Seki, Masafumi, Kimura, Shunsuke, Hiwatari, Mitsuteru, Kato, Motohiro, Fukuda, Shiro, Tatsuno, Kenji, Tsutsumi, Shuichi, Kanai, Akinori, Inaba, Toshiya, Shiozawa, Yusuke, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Kotecha, Rishi S., Cruickshank, Mark N., Ishikawa, Fumihiko, Morio, Tomohiro, Eguchi, Mariko, Deguchi, Takao, Kiyokawa, Nobutaka, Arakawa, Yuki, Koh, Katsuyoshi, Aoki, Yuki, Ishihara, Takashi, Tomizawa, Daisuke, Miyamura, Takako, Ishii, Eiichi, Mizutani, Shuki, Wilson, Nicola K., Göttgens, Berthold, Miyano, Satoru, Kitamura, Toshio, Goyama, Susumu, Yokoyama, Akihiko, Aburatani, Hiroyuki, Ogawa, Seishi, and Takita, Junko

Published
2022
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5. Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

Author

Tanaka, Yosuke, Takeda, Reina, Fukushima, Tsuyoshi, Mikami, Keiko, Tsuchiya, Shun, Tamura, Moe, Adachi, Keito, Umemoto, Terumasa, Asada, Shuhei, Watanabe, Naoki, Morishita, Soji, Imai, Misa, Nagata, Masayoshi, Araki, Marito, Takizawa, Hitoshi, Fukuyama, Tomofusa, Lamagna, Chrystelle, Masuda, Esteban S., Ito, Ryoji, Goyama, Susumu, Komatsu, Norio, Takaku, Tomoiku, and Kitamura, Toshio

Published
2022
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6. HHEX promotes myeloid transformation in cooperation with mutant ASXL1

Author

Takeda, Reina, Asada, Shuhei, Park, Sung-Joon, Yokoyama, Akihiko, Becker, Hans Jiro, Kanai, Akinori, Visconte, Valeria, Hershberger, Courtney, Hayashi, Yasutaka, Yonezawa, Taishi, Tamura, Moe, Fukushima, Tsuyoshi, Tanaka, Yosuke, Fukuyama, Tomofusa, Matsumoto, Akiko, Yamasaki, Satoshi, Nakai, Kenta, Yamazaki, Satoshi, Inaba, Toshiya, Shibata, Tatsuhiro, Inoue, Daichi, Honda, Hiroaki, Goyama, Susumu, Maciejewski, Jaroslaw P., and Kitamura, Toshio

Published
2020
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7. Supplemental Table S1 from Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities

Author

Ito, Ken, primary, Yamaguchi, Masayuki, primary, Semba, Taro, primary, Tabata, Kimiyo, primary, Tamura, Moe, primary, Aoyama, Muneo, primary, Abe, Takanori, primary, Asano, Osamu, primary, Terada, Yasuhiko, primary, Funahashi, Yasuhiro, primary, and Fujii, Hirofumi, primary

Published
2024
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8. Supplementary Fig. S9 from Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities

Author

Ito, Ken, primary, Yamaguchi, Masayuki, primary, Semba, Taro, primary, Tabata, Kimiyo, primary, Tamura, Moe, primary, Aoyama, Muneo, primary, Abe, Takanori, primary, Asano, Osamu, primary, Terada, Yasuhiko, primary, Funahashi, Yasuhiro, primary, and Fujii, Hirofumi, primary

Published
2024
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11. Amelioration of Tumor-Promoting Microenvironment via Vascular Remodeling and CAF Suppression using E7130: Biomarker Analysis by Multi-modal Imaging Modalities

Author

Ito, Ken, primary, Yamaguchi, Masayuki, additional, Semba, Taro, additional, Tabata, Kimiyo, additional, Tamura, Moe, additional, Aoyama, Muneo, additional, Abe, Takanori, additional, Asano, Osamu, additional, Terada, Yasuhiko, additional, Funahashi, Yasuhiro, additional, and Fujii, Hirofumi, additional

Published
2023
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15. Data from Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

Author

Osumi, Tomoo, primary, Tsujimoto, Shin-ichi, primary, Tamura, Moe, primary, Uchiyama, Meri, primary, Nakabayashi, Kazuhiko, primary, Okamura, Kohji, primary, Yoshida, Masanori, primary, Tomizawa, Daisuke, primary, Watanabe, Akihiro, primary, Takahashi, Hiroyuki, primary, Hori, Tsukasa, primary, Yamamoto, Shohei, primary, Hamamoto, Kazuko, primary, Migita, Masahiro, primary, Ogata-Kawata, Hiroko, primary, Uchiyama, Toru, primary, Kizawa, Hiroe, primary, Ueno-Yokohata, Hitomi, primary, Shirai, Ryota, primary, Seki, Masafumi, primary, Ohki, Kentaro, primary, Takita, Junko, primary, Inukai, Takeshi, primary, Ogawa, Seishi, primary, Kitamura, Toshio, primary, Matsumoto, Kimikazu, primary, Hata, Kenichiro, primary, Kiyokawa, Nobutaka, primary, Goyama, Susumu, primary, and Kato, Motohiro, primary

Published
2023
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16. Supplementary Information from Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

Author

Osumi, Tomoo, primary, Tsujimoto, Shin-ichi, primary, Tamura, Moe, primary, Uchiyama, Meri, primary, Nakabayashi, Kazuhiko, primary, Okamura, Kohji, primary, Yoshida, Masanori, primary, Tomizawa, Daisuke, primary, Watanabe, Akihiro, primary, Takahashi, Hiroyuki, primary, Hori, Tsukasa, primary, Yamamoto, Shohei, primary, Hamamoto, Kazuko, primary, Migita, Masahiro, primary, Ogata-Kawata, Hiroko, primary, Uchiyama, Toru, primary, Kizawa, Hiroe, primary, Ueno-Yokohata, Hitomi, primary, Shirai, Ryota, primary, Seki, Masafumi, primary, Ohki, Kentaro, primary, Takita, Junko, primary, Inukai, Takeshi, primary, Ogawa, Seishi, primary, Kitamura, Toshio, primary, Matsumoto, Kimikazu, primary, Hata, Kenichiro, primary, Kiyokawa, Nobutaka, primary, Goyama, Susumu, primary, and Kato, Motohiro, primary

Published
2023
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17. IMPDH inhibition activates TLR‐VCAM1 pathway and suppresses the development of MLL‐fusion leukemia

Author

Liu, Xiaoxiao, primary, Sato, Naru, additional, Yabushita, Tomohiro, additional, Li, Jingmei, additional, Jia, Yuhan, additional, Tamura, Moe, additional, Asada, Shuhei, additional, Fujino, Takeshi, additional, Fukushima, Tsuyoshi, additional, Yonezawa, Taishi, additional, Tanaka, Yosuke, additional, Fukuyama, Tomofusa, additional, Tsuchiya, Akiho, additional, Shikata, Shiori, additional, Iwamura, Hiroyuki, additional, Kinouchi, Chieko, additional, Komatsu, Kensuke, additional, Yamasaki, Satoshi, additional, Shibata, Tatsuhiro, additional, Sasaki, Atsuo T, additional, Schibler, Janet, additional, Wunderlich, Mark, additional, O'Brien, Eric, additional, Mizukawa, Benjamin, additional, Mulloy, James C, additional, Sugiura, Yuki, additional, Takizawa, Hitoshi, additional, Shibata, Takuma, additional, Miyake, Kensuke, additional, Kitamura, Toshio, additional, and Goyama, Susumu, additional

Published
2022
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18. Hyperactive NK cells in Rag2 knockout mice inhibit the development of acute myeloid leukemia

Author

Sugimoto, Emi, primary, Hayashi, Yasutakka, additional, Iida, Kohei, additional, Asada, Shuhei, additional, Fukushima, Tsuyoshi, additional, Tamura, Moe, additional, Kawabata, Kimihito, additional, Kawase, Tatsuya, additional, Saito, Takeshi, additional, Yoshida, Taku, additional, Yamazaki, Satoshi, additional, Kaito, Yuta, additional, Imai, Yoich, additional, Fukuyama, Tomofusa, additional, Tanaka, Yosuke, additional, Enomoto, Yutaka, additional, Kitamura, Toshio, additional, and Goyama, Susumu, additional

Published
2022
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19. Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

Author

60451811, 00359621, Isobe, Tomoya, Takagi, Masatoshi, Sato-Otsubo, Aiko, Nishimura, Akira, Nagae, Genta, Yamagishi, Chika, Tamura, Moe, Tanaka, Yosuke, Asada, Shuhei, Takeda, Reina, Tsuchiya, Akiho, Wang, Xiaonan, Yoshida, Kenichi, Nannya, Yasuhito, Ueno, Hiroo, Akazawa, Ryo, Kato, Itaru, Mikami, Takashi, Watanabe, Kentaro, Sekiguchi, Masahiro, Seki, Masafumi, Kimura, Shunsuke, Hiwatari, Mitsuteru, Kato, Motohiro, Fukuda, Shiro, Tatsuno, Kenji, Tsutsumi, Shuichi, Kanai, Akinori, Inaba, Toshiya, Shiozawa, Yusuke, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Kotecha, Rishi S., Cruickshank, Mark N., Ishikawa, Fumihiko, Morio, Tomohiro, Eguchi, Mariko, Deguchi, Takao, Kiyokawa, Nobutaka, Arakawa, Yuki, Koh, Katsuyoshi, Aoki, Yuki, Ishihara, Takashi, Tomizawa, Daisuke, Miyamura, Takako, Ishii, Eiichi, Mizutani, Shuki, Wilson, Nicola K., Göttgens, Berthold, Miyano, Satoru, Kitamura, Toshio, Goyama, Susumu, Yokoyama, Akihiko, Aburatani, Hiroyuki, Ogawa, Seishi, Takita, Junko, 60451811, 00359621, Isobe, Tomoya, Takagi, Masatoshi, Sato-Otsubo, Aiko, Nishimura, Akira, Nagae, Genta, Yamagishi, Chika, Tamura, Moe, Tanaka, Yosuke, Asada, Shuhei, Takeda, Reina, Tsuchiya, Akiho, Wang, Xiaonan, Yoshida, Kenichi, Nannya, Yasuhito, Ueno, Hiroo, Akazawa, Ryo, Kato, Itaru, Mikami, Takashi, Watanabe, Kentaro, Sekiguchi, Masahiro, Seki, Masafumi, Kimura, Shunsuke, Hiwatari, Mitsuteru, Kato, Motohiro, Fukuda, Shiro, Tatsuno, Kenji, Tsutsumi, Shuichi, Kanai, Akinori, Inaba, Toshiya, Shiozawa, Yusuke, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Kotecha, Rishi S., Cruickshank, Mark N., Ishikawa, Fumihiko, Morio, Tomohiro, Eguchi, Mariko, Deguchi, Takao, Kiyokawa, Nobutaka, Arakawa, Yuki, Koh, Katsuyoshi, Aoki, Yuki, Ishihara, Takashi, Tomizawa, Daisuke, Miyamura, Takako, Ishii, Eiichi, Mizutani, Shuki, Wilson, Nicola K., Göttgens, Berthold, Miyano, Satoru, Kitamura, Toshio, Goyama, Susumu, Yokoyama, Akihiko, Aburatani, Hiroyuki, Ogawa, Seishi, and Takita, Junko

Abstract

KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.

Published
2022

20. IMPDH inhibition activates TLR‐VCAM1 pathway and suppresses the development of MLL‐fusion leukemia.

Author

Liu, Xiaoxiao, Sato, Naru, Yabushita, Tomohiro, Li, Jingmei, Jia, Yuhan, Tamura, Moe, Asada, Shuhei, Fujino, Takeshi, Fukushima, Tsuyoshi, Yonezawa, Taishi, Tanaka, Yosuke, Fukuyama, Tomofusa, Tsuchiya, Akiho, Shikata, Shiori, Iwamura, Hiroyuki, Kinouchi, Chieko, Komatsu, Kensuke, Yamasaki, Satoshi, Shibata, Tatsuhiro, and Sasaki, Atsuo T

Abstract

Inosine monophosphate dehydrogenase (IMPDH) is a rate‐limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL‐fusions are susceptible to IMPDH inhibitors in vitro. We also showed that alternate‐day administration of IMPDH inhibitors suppressed the development of MLL‐AF9‐driven AML in vivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll‐like receptor (TLR)‐TRAF6‐NF‐κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL‐fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL‐fusion AMLs and potentially other aggressive tumors with active TLR signaling. Synopsis: This study describes the potent antileukemia effect of IMPDH inhibitors on MLL‐fusion leukemias, which is partly mediated by the overactivation of TLR‐NF‐kB‐Vcam1 pathway. MLL‐fusion leukemias are particularly susceptible to IMPDH inhibition.An alternate‐day administration of IMPDH inhibitors effectively suppresses MLL‐AF9‐driven leukemogenesis in vivo through myeloid differentiation without any devastating effect on immune function.IMPDH inhibition results in activation of TLR pathway and Vcam1 upregulation in MLL‐fusion leukemia cells.Combined treatment with IMPDH inhibitors and the TLR1/2 agonist shows potent antileukemia effects in vivo. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Eradicating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

Author

Tanaka, Yosuke, primary, Fukushima, Tsuyoshi, additional, Mikami, Keiko, additional, Tsuchiya, Shun, additional, Tamura, Moe, additional, Adachi, Keito, additional, Umemoto, Terumasa, additional, Watanabe, Naoki, additional, Morishita, Soji, additional, Imai, Misa, additional, Nagasawa, Masayoshi, additional, Araki, Marito, additional, Takizawa, Hitoshi, additional, Fukuyama, Tomofusa, additional, Lamagna, Chrystelle, additional, Masuda, Esteban, additional, Ito, Ryoji, additional, Goyama, Susumu, additional, Komatsu, Norio, additional, Takaku, Tomoiku, additional, and Kitamura, Toshio, additional

Published
2021
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22. Impaired Osteoblastic Differentiation of MSCs Suppresses Normal Hematopoiesis in MDS

Author

Hayashi, Yasutaka, primary, Kawabata, Kimihito Cojin, additional, Tanaka, Yosuke, additional, Uehara, Yasufumi, additional, Kiryu, Shigeru, additional, Ota, Yasunori, additional, Yoshioka, Yusuke, additional, Mabuchi, Yo, additional, Sugiyama, Tatsuki, additional, Mikami, Keiko, additional, Tamura, Moe, additional, Fukushima, Tsuyoshi, additional, Asada, Shuhei, additional, Takeda, Reina, additional, Kunisaki, Yuya, additional, Fukuyama, Tomofusa, additional, Goyama, Susumu, additional, Yokoyama, Kazuaki, additional, Tojo, Arinobu, additional, Katayama, Yoshio, additional, Arai, Fumio, additional, Nagasawa, Takashi, additional, Ochiya, Takahiro, additional, Inoue, Daichi, additional, and Kitamura, Toshio, additional

Published
2020
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24. Homeobox Transcription Factor Hhex Promotes Myeloid Leukemia in Cooperation with Mutant ASXL1

Author

Takeda, Reina, primary, Asada, Shuhei, additional, Park, Sung-Joon, additional, Yokoyama, Akihiko, additional, Kanai, Akinori, additional, Visconte, Valeria, additional, Hershberger, Courtney, additional, Hayashi, Yasutaka, additional, Yonezawa, Taishi, additional, Tamura, Moe, additional, Fukuyama, Tomofusa, additional, Matsumoto, Akiko, additional, Yamasaki, Satoshi, additional, Nakai, Kenta, additional, Inaba, Toshiya, additional, Shibata, Tatsuhiro, additional, Inoue, Daichi, additional, Honda, Hiroaki, additional, Goyama, Susumu, additional, Maciejewski, Jaroslaw P., additional, and Kitamura, Toshio, additional

Published
2019
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25. Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

Author

Osumi, Tomoo, primary, Tsujimoto, Shin-ichi, additional, Tamura, Moe, additional, Uchiyama, Meri, additional, Nakabayashi, Kazuhiko, additional, Okamura, Kohji, additional, Yoshida, Masanori, additional, Tomizawa, Daisuke, additional, Watanabe, Akihiro, additional, Takahashi, Hiroyuki, additional, Hori, Tsukasa, additional, Yamamoto, Shohei, additional, Hamamoto, Kazuko, additional, Migita, Masahiro, additional, Ogata-Kawata, Hiroko, additional, Uchiyama, Toru, additional, Kizawa, Hiroe, additional, Ueno-Yokohata, Hitomi, additional, Shirai, Ryota, additional, Seki, Masafumi, additional, Ohki, Kentaro, additional, Takita, Junko, additional, Inukai, Takeshi, additional, Ogawa, Seishi, additional, Kitamura, Toshio, additional, Matsumoto, Kimikazu, additional, Hata, Kenichiro, additional, Kiyokawa, Nobutaka, additional, Goyama, Susumu, additional, and Kato, Motohiro, additional

Published
2018
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28. RARB Translocations in Acute Promyelocytic Leukemia without Rara translocation

Author

Kato, Motohiro, Osumi, Tomoo, Tsujimoto, Shinichi, Tamura, Moe, Uchiyama, Meri, Nakabayashi, Kazuhiko, Okamura, Kohji, Tomizawa, Daisuke, Watanabe, Akihiro, Takahashi, Hiroyuki, Hori, Tsukasa, Yamamoto, Shohei, Hamamoto, Kazuko, Migita, Masahiro, Ogata-Kawata, Hiroko, Uchiyama, Toru, Kizawa, Hiroe, Ueno-Yokohata, Hitomi, Shirai, Ryota, Yoshida, Masanori, Seki, Masafumi, Oki, Kentaro, Takita, Junko, Ogawa, Seishi, Kitamura, Toshio, Matsumoto, Kimikazu, Hata, Kenichiro, Goyama, Susumu, and Kiyokawa, Nobutaka

Published
2017
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29. RARBTranslocations in Acute Promyelocytic Leukemia without Raratranslocation

Author

Kato, Motohiro, Osumi, Tomoo, Tsujimoto, Shinichi, Tamura, Moe, Uchiyama, Meri, Nakabayashi, Kazuhiko, Okamura, Kohji, Tomizawa, Daisuke, Watanabe, Akihiro, Takahashi, Hiroyuki, Hori, Tsukasa, Yamamoto, Shohei, Hamamoto, Kazuko, Migita, Masahiro, Ogata-Kawata, Hiroko, Uchiyama, Toru, Kizawa, Hiroe, Ueno-Yokohata, Hitomi, Shirai, Ryota, Yoshida, Masanori, Seki, Masafumi, Oki, Kentaro, Takita, Junko, Ogawa, Seishi, Kitamura, Toshio, Matsumoto, Kimikazu, Hata, Kenichiro, Goyama, Susumu, and Kiyokawa, Nobutaka

Abstract

Introduction: Acute promyelocytic leukemia (APL) is defined by unique morphological features, typically abnormal promyelocytes containing azurophilic granules. Genomic basis of APL is characterized by the translocation t(15;17)(q22;q21), inducing fusions between promyelocytic leukemia (PML) and retinoic acid receptor-a (RARA). APL cells with PML-RARA respond to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), and recent clinical trials have achieved excellent outcome for typical APL with PML-RARA. Although a certain fraction of APL cases lacks PMR-RARA, most of them had translocation including RARAand other genes, namely, PLZF, NPM, and TBL1XR1. Eventually, all known APL-associated translocations involve RARA, accounting for 99% of APL. However, RARArearrangement is unable to be detected in the rest of APL cases, and molecular mechanisms underlying this small subset is still unclear. We here analyzed APL cases without RARAtranslocation, and identified a novel RARBfusion in the majority of patients with RARA-negative APL.

Published
2017
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30. Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities.

Author

Ito K, Yamaguchi M, Semba T, Tabata K, Tamura M, Aoyama M, Abe T, Asano O, Terada Y, Funahashi Y, and Fujii H

Subjects
Animals, Humans, Vascular Remodeling, Tumor Microenvironment, Endothelial Cells pathology, Cancer-Associated Fibroblasts pathology, Neoplasms drug therapy, Neoplasms, Experimental, Antimitotic Agents pharmacology
Abstract

E7130 is a novel anticancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAF) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging modalities, including multiplexed mass cytometry [cytometry by time-of-flight (CyTOF)] analysis, multiplex IHC analysis, and MRI. Experimental solid tumors characterized by large numbers of CAFs in TME were treated with E7130. E7130 suppressed LAP-TGFβ1 production, a precursor of TGFβ1, in CAFs but not in cancer cells; an effect that was accompanied by a reduction of circulating TGFβ1 in plasma. To our best knowledge, this is the first report to show a reduction of TGFβ1 production in TME. Furthermore, multiplex IHC analysis revealed reduced cellularity and increased TUNEL-positive apoptotic cells in E7130-treated xenografts. Increased microvessel density (MVD) and collagen IV (Col IV), an extracellular matrix (ECM) component associated with endothelial cells, were also observed in the TME, and plasma Col IV levels were also increased by E7130 treatment. MRI revealed increased accumulation of a contrast agent in xenografts. Moreover, diffusion-weighted MRI after E7130 treatment indicated reduction of tumor cellularity and interstitial fluid pressure. Overall, our findings strongly support the mechanism of action that E7130 alters the TME in therapeutically beneficial ways. Importantly, from a translational perspective, our data demonstrated MRI as a noninvasive biomarker to detect TME amelioration by E7130, supported by consistent changes in plasma biomarkers., (©2023 American Association for Cancer Research.)

Published
2024
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