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420 results on '"Yoshimi, Akihide"'

1. Mechanistic insights into lethal hyper progressive disease induced by PD-L1 inhibitor in metastatic urothelial carcinoma

Author

Nishimura, Kazuki, Takahara, Kiyoshi, Komura, Kazumasa, Ishida, Mitsuaki, Hirosuna, Kensuke, Maenosono, Ryoichi, Ajiro, Masahiko, Sakamoto, Moritoshi, Iwatsuki, Kengo, Nakajima, Yuki, Tsujino, Takuya, Taniguchi, Kohei, Tanaka, Tomohito, Inamoto, Teruo, Hirose, Yoshinobu, Ono, Fumihito, Kondo, Yoichi, Yoshimi, Akihide, and Azuma, Haruhito

Published
2024
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2. Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization

Author

Kaito, Satoshi, Aoyama, Kazumasa, Oshima, Motohiko, Tsuchiya, Akiho, Miyota, Makiko, Yamashita, Masayuki, Koide, Shuhei, Nakajima-Takagi, Yaeko, Kozuka-Hata, Hiroko, Oyama, Masaaki, Yogo, Takao, Yabushita, Tomohiro, Ito, Ryoji, Ueno, Masaya, Hirao, Atsushi, Tohyama, Kaoru, Li, Chao, Kawabata, Kimihito Cojin, Yamaguchi, Kiyoshi, Furukawa, Yoichi, Kosako, Hidetaka, Yoshimi, Akihide, Goyama, Susumu, Nannya, Yasuhito, Ogawa, Seishi, Agger, Karl, Helin, Kristian, Yamazaki, Satoshi, Koseki, Haruhiko, Doki, Noriko, Harada, Yuka, Harada, Hironori, Nishiyama, Atsuya, Nakanishi, Makoto, and Iwama, Atsushi

Published
2024
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4. Disruption of cotranscriptional splicing suggests RBM39 is a therapeutic target in acute lymphoblastic leukemia

Author

Jin, Qi, Harris, Ethan, Myers, Jacquelyn A., Mehmood, Rashid, Cotton, Anitria, Shirnekhi, Hazheen K., Baggett, David W., Wen, Jeremy Qiang, Schild, Andrew B., Bhansali, Rahul S., Klein, Jonathon, Narina, Shilpa, Pieters, Tim, Yoshimi, Akihide, Pruett-Miller, Shondra M., Kriwacki, Richard, Abdel-Wahab, Omar, Malinge, Sebastien, Ntziachristos, Panagiotis, Obeng, Esther A., and Crispino, John D.

Published
2024
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5. The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer

Author

Komura, Kazumasa, Hirosuna, Kensuke, Tokushige, Satoshi, Tsujino, Takuya, Nishimura, Kazuki, Ishida, Mitsuaki, Hayashi, Takuo, Ura, Ayako, Ohno, Takaya, Yamazaki, Shogo, Nakamori, Keita, Kinoshita, Shoko, Maenosono, Ryoichi, Ajiro, Masahiko, Yoshikawa, Yuki, Takai, Tomoaki, Tsutsumi, Takeshi, Taniguchi, Kohei, Tanaka, Tomohito, Takahara, Kiyoshi, Konuma, Tsuyoshi, Inamoto, Teruo, Hirose, Yoshinobu, Ono, Fumihito, Shiraishi, Yuichi, Yoshimi, Akihide, and Azuma, Haruhito

Published
2023
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12. Genetic basis for iMCD-TAFRO

Author

Yoshimi, Akihide, Trippett, Tanya M., Zhang, Nan, Chen, Xueyan, Penson, Alexander V., Arcila, Maria E., Pichardo, Janine, Baik, Jeeyeon, Sigler, Allison, Harada, Hironori, Fajgenbaum, David C., Dogan, Ahmet, Abdel-Wahab, Omar, and Xiao, Wenbin

Published
2020
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13. SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer

Author

Ma, Hai-Li, primary, Bizet, Martin, additional, Soares Da Costa, Christelle, additional, Murisier, Frédéric, additional, de Bony, Eric James, additional, Wang, Meng-Ke, additional, Yoshimi, Akihide, additional, Lin, Kuan-Ting, additional, Riching, Kristin M., additional, Wang, Xing, additional, Beckman, John I., additional, Arya, Shailee, additional, Droin, Nathalie, additional, Calonne, Emilie, additional, Hassabi, Bouchra, additional, Zhang, Qing-Yang, additional, Li, Ang, additional, Putmans, Pascale, additional, Malbec, Lionel, additional, Hubert, Céline, additional, Lan, Jie, additional, Mies, Frédérique, additional, Yang, Ying, additional, Solary, Eric, additional, Daniels, Danette L., additional, Gupta, Yogesh K., additional, Deplus, Rachel, additional, Abdel-Wahab, Omar, additional, Yang, Yun-Gui, additional, and Fuks, François, additional

Published
2023
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15. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis

Author

Yoshimi, Akihide, Lin, Kuan-Ting, Wiseman, Daniel H., Rahman, Mohammad Alinoor, Pastore, Alessandro, Wang, Bo, and Lee, Stanley Chun-Wei

Subjects
Leukemia -- Development and progression -- Genetic aspects, RNA splicing -- Methods, Epigenetic inheritance -- Control, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia.sup.1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex.sup.3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis. Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2, which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing., Author(s): Akihide Yoshimi [sup.1] , Kuan-Ting Lin [sup.2] , Daniel H. Wiseman [sup.3] [sup.4] , Mohammad Alinoor Rahman [sup.2] , Alessandro Pastore [sup.1] , Bo Wang [sup.1] , Stanley Chun-Wei [...]

Published
2019
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16. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms

Author

Durham, Benjamin H., Lopez Rodrigo, Estibaliz, Picarsic, Jennifer, Abramson, David, Rotemberg, Veronica, De Munck, Steven, Pannecoucke, Erwin, Lu, Sydney X., Pastore, Alessandro, Yoshimi, Akihide, Mandelker, Diana, Ceyhan-Birsoy, Ozge, Ulaner, Gary A., Walsh, Michael, Yabe, Mariko, Petrova-Drus, Kseniya, Arcila, Maria E., Ladanyi, Marc, Solit, David B., Berger, Michael F., Hyman, David M., Lacouture, Mario E., Erickson, Caroline, Saganty, Ruth, Ki, Michelle, Dunkel, Ira J., Santa-María López, Vicente, Mora, Jaume, Haroche, Julien, Emile, Jean-Francois, Decaux, Olivier, Geissmann, Frederic, Savvides, Savvas N., Drilon, Alexander, Diamond, Eli L., and Abdel-Wahab, Omar

Published
2019
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17. Spliceosomal disruption of the non-canonical BAF complex in cancer

Author

Inoue, Daichi, Chew, Guo-Liang, Liu, Bo, Michel, Brittany C., Pangallo, Joseph, D’Avino, Andrew R., Hitchman, Tyler, North, Khrystyna, Lee, Stanley Chun-Wei, Bitner, Lillian, Block, Ariele, Moore, Amanda R., Yoshimi, Akihide, Escobar-Hoyos, Luisa, Cho, Hana, Penson, Alex, Lu, Sydney X., Taylor, Justin, Chen, Yu, Kadoch, Cigall, Abdel-Wahab, Omar, and Bradley, Robert K.

Published
2019
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19. Tertiary lymphoid structure and neutrophil–lymphocyte ratio coordinately predict outcome of pembrolizumab

Author

Komura, Kazumasa, primary, Tokushige, Satoshi, additional, Ishida, Mitsuaki, additional, Hirosuna, Kensuke, additional, Yamazaki, Shogo, additional, Nishimura, Kazuki, additional, Ajiro, Masahiko, additional, Ohno, Takaya, additional, Nakamori, Keita, additional, Kinoshita, Shoko, additional, Tsujino, Takuya, additional, Maenosono, Ryoichi, additional, Yoshikawa, Yuki, additional, Takai, Tomoaki, additional, Tsutsumi, Takeshi, additional, Taniguchi, Kohei, additional, Tanaka, Tomohito, additional, Takahara, Kiyoshi, additional, Inamoto, Teruo, additional, Hirose, Yoshinobu, additional, Ono, Fumihito, additional, Shiraishi, Yuichi, additional, Yoshimi, Akihide, additional, and Azuma, Haruhito, additional

Published
2023
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21. Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Author

Yoshimi, Akihide, Balasis, Maria E., Vedder, Alexis, Feldman, Kira, Ma, Yan, Zhang, Hailing, Lee, Stanley Chun-Wei, Letson, Christopher, Niyongere, Sandrine, Lu, Sydney X., Ball, Markus, Taylor, Justin, Zhang, Qing, Zhao, Yulong, Youssef, Salma, Chung, Young Rock, Zhang, Xiao Jing, Durham, Benjamin H., Yang, Wendy, List, Alan F., Loh, Mignon L., Klimek, Virginia, Berger, Michael F., Stieglitz, Elliot, Padron, Eric, and Abdel-Wahab, Omar

Published
2017
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22. Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies

Author

Taylor, Justin, Pavlick, Dean, Yoshimi, Akihide, Marcelus, Christina, Chung, Stephen S., Hechtman, Jaclyn F., Benayed, Ryma, Cocco, Emiliano, Durham, Benjamin H., Bitner, Lillian, Inoue, Daichi, Chung, Young Rock, Mullaney, Kerry, Watts, Justin M., Diamond, Eli L., Albacker, Lee A., Mughal, Tariq I., Ebata, Kevin, Tuch, Brian B., Ku, Nora, Scaltriti, Maurizio, Roshal, Mikhail, Arcila, Maria, Ali, Siraj, Hyman, David M., Park, Jae H., and Abdel-Wahab, Omar

Subjects
Protein-tyrosine kinase -- Physiological aspects -- Health aspects, Cancer genetics -- Research, Kinase inhibitors -- Research, Medical research, Hematologic diseases -- Genetic aspects -- Development and progression, Health care industry
Abstract

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition., Introduction Fusions involving neurotrophic receptor tyrosine kinases (NTRKs) were among the first gene translocations described in cancer (1, 2). NTRK1, NTRK2, and NTRK3 (encoding TrkA, TrkB, and TrkC, respectively; hereafter [...]

Published
2018
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23. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers

Author

Seiler, Michael, Yoshimi, Akihide, Darman, Rachel, Chan, Betty, Keaney, Gregg, Thomas, Michael, Agrawal, Anant A, Caleb, Benjamin, Csibi, Alfredo, Sean, Eckley, Fekkes, Peter, Karr, Craig, Klimek, Virginia, Lai, George, Lee, Linda, Kumar, Pavan, Lee, Stanley Chun-Wei, Liu, Xiang, Mackenzie, Crystal, Meeske, Carol, Mizui, Yoshiharu, Padron, Eric, Park, Eunice, Pazolli, Ermira, Peng, Shouyong, Prajapati, Sudeep, Taylor, Justin, Teng, Teng, Wang, John, Warmuth, Markus, Yao, Huilan, Yu, Lihua, Zhu, Ping, Abdel-Wahab, Omar, Smith, Peter G, and Buonamici, Silvia

Subjects
RNA splicing -- Health aspects, Gene mutation -- Health aspects, Carcinogenesis -- Genetic aspects, Biological sciences, Health
Abstract

Author(s): Michael Seiler [1]; Akihide Yoshimi [2]; Rachel Darman [1]; Betty Chan [1]; Gregg Keaney [1]; Michael Thomas [1]; Anant A Agrawal [1]; Benjamin Caleb [1]; Alfredo Csibi [1]; Eckley [...]

Published
2018
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24. Table S5 from Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis

Author

Taylor, Justin, primary, Sendino, Maria, primary, Gorelick, Alexander N., primary, Pastore, Alessandro, primary, Chang, Matthew T., primary, Penson, Alexander V., primary, Gavrila, Elena I., primary, Stewart, Connor, primary, Melnik, Ella M., primary, Herrejon Chavez, Florisela, primary, Bitner, Lillian, primary, Yoshimi, Akihide, primary, Lee, Stanley Chun-Wei, primary, Inoue, Daichi, primary, Liu, Bo, primary, Zhang, Xiao J., primary, Mato, Anthony R., primary, Dogan, Ahmet, primary, Kharas, Michael G., primary, Chen, Yuhong, primary, Wang, Demin, primary, Soni, Rajesh K., primary, Hendrickson, Ronald C., primary, Prieto, Gorka, primary, Rodriguez, Jose A., primary, Taylor, Barry S., primary, and Abdel-Wahab, Omar, primary

Published
2023
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25. Data from Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis

Author

Taylor, Justin, primary, Sendino, Maria, primary, Gorelick, Alexander N., primary, Pastore, Alessandro, primary, Chang, Matthew T., primary, Penson, Alexander V., primary, Gavrila, Elena I., primary, Stewart, Connor, primary, Melnik, Ella M., primary, Herrejon Chavez, Florisela, primary, Bitner, Lillian, primary, Yoshimi, Akihide, primary, Lee, Stanley Chun-Wei, primary, Inoue, Daichi, primary, Liu, Bo, primary, Zhang, Xiao J., primary, Mato, Anthony R., primary, Dogan, Ahmet, primary, Kharas, Michael G., primary, Chen, Yuhong, primary, Wang, Demin, primary, Soni, Rajesh K., primary, Hendrickson, Ronald C., primary, Prieto, Gorka, primary, Rodriguez, Jose A., primary, Taylor, Barry S., primary, and Abdel-Wahab, Omar, primary

Published
2023
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26. Supplementary Figures from Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis

Author

Taylor, Justin, primary, Sendino, Maria, primary, Gorelick, Alexander N., primary, Pastore, Alessandro, primary, Chang, Matthew T., primary, Penson, Alexander V., primary, Gavrila, Elena I., primary, Stewart, Connor, primary, Melnik, Ella M., primary, Herrejon Chavez, Florisela, primary, Bitner, Lillian, primary, Yoshimi, Akihide, primary, Lee, Stanley Chun-Wei, primary, Inoue, Daichi, primary, Liu, Bo, primary, Zhang, Xiao J., primary, Mato, Anthony R., primary, Dogan, Ahmet, primary, Kharas, Michael G., primary, Chen, Yuhong, primary, Wang, Demin, primary, Soni, Rajesh K., primary, Hendrickson, Ronald C., primary, Prieto, Gorka, primary, Rodriguez, Jose A., primary, Taylor, Barry S., primary, and Abdel-Wahab, Omar, primary

Published
2023
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27. Data from Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization

Author

Liu, Zhaoqi, primary, Yoshimi, Akihide, primary, Wang, Jiguang, primary, Cho, Hana, primary, Chun-Wei Lee, Stanley, primary, Ki, Michelle, primary, Bitner, Lillian, primary, Chu, Timothy, primary, Shah, Harshal, primary, Liu, Bo, primary, Mato, Anthony R., primary, Ruvolo, Peter, primary, Fabbri, Giulia, primary, Pasqualucci, Laura, primary, Abdel-Wahab, Omar, primary, and Rabadan, Raul, primary

Published
2023
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28. Supplementary Data from Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization

Author

Liu, Zhaoqi, primary, Yoshimi, Akihide, primary, Wang, Jiguang, primary, Cho, Hana, primary, Chun-Wei Lee, Stanley, primary, Ki, Michelle, primary, Bitner, Lillian, primary, Chu, Timothy, primary, Shah, Harshal, primary, Liu, Bo, primary, Mato, Anthony R., primary, Ruvolo, Peter, primary, Fabbri, Giulia, primary, Pasqualucci, Laura, primary, Abdel-Wahab, Omar, primary, and Rabadan, Raul, primary

Published
2023
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29. Supplementary Methods from Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis

Author

Taylor, Justin, primary, Sendino, Maria, primary, Gorelick, Alexander N., primary, Pastore, Alessandro, primary, Chang, Matthew T., primary, Penson, Alexander V., primary, Gavrila, Elena I., primary, Stewart, Connor, primary, Melnik, Ella M., primary, Herrejon Chavez, Florisela, primary, Bitner, Lillian, primary, Yoshimi, Akihide, primary, Lee, Stanley Chun-Wei, primary, Inoue, Daichi, primary, Liu, Bo, primary, Zhang, Xiao J., primary, Mato, Anthony R., primary, Dogan, Ahmet, primary, Kharas, Michael G., primary, Chen, Yuhong, primary, Wang, Demin, primary, Soni, Rajesh K., primary, Hendrickson, Ronald C., primary, Prieto, Gorka, primary, Rodriguez, Jose A., primary, Taylor, Barry S., primary, and Abdel-Wahab, Omar, primary

Published
2023
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30. Supplementary Table Captions from Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis

Author

Taylor, Justin, primary, Sendino, Maria, primary, Gorelick, Alexander N., primary, Pastore, Alessandro, primary, Chang, Matthew T., primary, Penson, Alexander V., primary, Gavrila, Elena I., primary, Stewart, Connor, primary, Melnik, Ella M., primary, Herrejon Chavez, Florisela, primary, Bitner, Lillian, primary, Yoshimi, Akihide, primary, Lee, Stanley Chun-Wei, primary, Inoue, Daichi, primary, Liu, Bo, primary, Zhang, Xiao J., primary, Mato, Anthony R., primary, Dogan, Ahmet, primary, Kharas, Michael G., primary, Chen, Yuhong, primary, Wang, Demin, primary, Soni, Rajesh K., primary, Hendrickson, Ronald C., primary, Prieto, Gorka, primary, Rodriguez, Jose A., primary, Taylor, Barry S., primary, and Abdel-Wahab, Omar, primary

Published
2023
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31. SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.

Author

Ma, Haili, Bizet, Martin, Soares Da Costa, Christelle, Murisier, Frédéric, de Bony, Eric James, Wang, Meng-Ke, Yoshimi, Akihide, Lin, Kuan-Ting, Riching, Kristin M., Wang, Xing, Beckman, John I., Arya, Shailee, Droin, Nathalie, Calonne, Emilie, Hassabi, Bouchra, Zhang, Qing-Yang, Li, Ang, Putmans, Pascale, Malbec, Lionel, Hubert, Céline, Lan, Jie, Mies, Frédérique, Bula Ibula Yanga, Yanga, Solary, Eric, Daniels, Danette, Gupta, Yogesh K., Deplus, Rachel, Abdel-Wahab, Omar, Yang, Yun-Gui, Fuks, François, Ma, Haili, Bizet, Martin, Soares Da Costa, Christelle, Murisier, Frédéric, de Bony, Eric James, Wang, Meng-Ke, Yoshimi, Akihide, Lin, Kuan-Ting, Riching, Kristin M., Wang, Xing, Beckman, John I., Arya, Shailee, Droin, Nathalie, Calonne, Emilie, Hassabi, Bouchra, Zhang, Qing-Yang, Li, Ang, Putmans, Pascale, Malbec, Lionel, Hubert, Céline, Lan, Jie, Mies, Frédérique, Bula Ibula Yanga, Yanga, Solary, Eric, Daniels, Danette, Gupta, Yogesh K., Deplus, Rachel, Abdel-Wahab, Omar, Yang, Yun-Gui, and Fuks, François

Abstract

A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2023

32. Structural basis of cytokine-mediated activation of ALK family receptors

Author

De Munck, Steven, Provost, Mathias, Kurikawa, Michiko, Omori, Ikuko, Mukohyama, Junko, Felix, Jan, Bloch, Yehudi, Abdel-Wahab, Omar, Bazan, J. Fernando, Yoshimi, Akihide, and Savvides, Savvas N.

Abstract

Anaplastic lymphoma kinase (ALK)1and the related leukocyte tyrosine kinase (LTK)2are recently deorphanized receptor tyrosine kinases3. Together with their activating cytokines, ALKAL1 and ALKAL24–6(also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development7, cancer7–9and autoimmune diseases10. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain11, consistent with a metabolic role for DrosophilaALK12. Despite such functional pleiotropy and growing therapeutic relevance13,14, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure–function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases.

Published
2024
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36. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins

Author

Lee, Stanley Chun-Wei, Dvinge, Heidi, Kim, Eunhee, Cho, Hana, Micol, Jean-Baptiste, Chung, Young Rock, Durham, Benjamin H, Yoshimi, Akihide, Kim, Young Joon, Thomas, Michael, Lobry, Camille, Chen, Chun-Wei, Pastore, Alessandro, Taylor, Justin, Wang, Xujun, Krivtsov, Andrei, Armstrong, Scott A, Palacino, James, Buonamici, Silvia, Smith, Peter G, Bradley, Robert K, and Abdel-Wahab, Omar

Subjects
Catalysis -- Health aspects -- Research, Gene mutation -- Research, Leukemia -- Genetic aspects -- Risk factors -- Care and treatment, Biological sciences, Health
Abstract

Author(s): Stanley Chun-Wei Lee [1]; Heidi Dvinge [2, 3]; Eunhee Kim [1]; Hana Cho [1]; Jean-Baptiste Micol [1]; Young Rock Chung [1]; Benjamin H Durham [1]; Akihide Yoshimi [1]; Young [...]

Published
2016
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42. Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

Author

Kagoya, Yuki, Yoshimi, Akihide, Kataoka, Keisuke, Nakagawa, Masahiro, Kumano, Keiki, Arai, Shunya, Kobayashi, Hiroshi, Saito, Taku, Iwakura, Yoichiro, and Kurokawa, Mineo

Subjects
Tumor necrosis factor -- Physiological aspects -- Research, Cellular signal transduction -- Research, Cancer cells -- Physiological aspects -- Research, Health care industry
Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBo and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs., Introduction Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy characterized by a relentless proliferation of immature myeloid blasts. Recent studies have demonstrated that the apparently uniform leukemia cell [...]

Published
2014
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44. Efficient production of human neutrophils from iPSCs that prevent murine lethal infection with immune cell recruitment

Author

Miyauchi, Masashi, primary, Ito, Yusuke, additional, Nakahara, Fumio, additional, Hino, Toshiya, additional, Nakamura, Fumi, additional, Iwasaki, Yuki, additional, Kawagoshi, Taiki, additional, Koya, Junji, additional, Yoshimi, Akihide, additional, Arai, Shunya, additional, Kagoya, Yuki, additional, and Kurokawa, Mineo, additional

Published
2021
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