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1. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms

Author

Makishima, Hideki, Saiki, Ryunosuke, Nannya, Yasuhito, Korotev, Sophia, Gurnari, Carmelo, Takeda, June, Momozawa, Yukihide, Best, Steve, Krishnamurthy, Pramila, Yoshizato, Tetsuichi, Atsuta, Yoshiko, Shiozawa, Yusuke, Iijima-Yamashita, Yuka, Yoshida, Kenichi, Shiraishi, Yuichi, Nagata, Yasunobu, Kakiuchi, Nobuyuki, Onizuka, Makoto, Chiba, Kenichi, Tanaka, Hiroko, Kon, Ayana, Ochi, Yotaro, Nakagawa, Masahiro M., Okuda, Rurika, Mori, Takuto, Yoda, Akinori, Itonaga, Hidehiro, Miyazaki, Yasushi, Sanada, Masashi, Ishikawa, Takayuki, Chiba, Shigeru, Tsurumi, Hisashi, Kasahara, Senji, Muller-Tidow, Carsten, Takaori-Kondo, Akifumi, Ohyashiki, Kazuma, Kiguchi, Toru, Matsuda, Fumihiko, Jansen, Joop H., Polprasert, Chantana, Blombery, Piers, Kamatani, Yoichiro, Miyano, Satoru, Malcovati, Luca, Haferlach, Torsten, Kubo, Michiaki, Cazzola, Mario, Kulasekararaj, Austin G., Godley, Lucy A., Maciejewski, Jaroslaw P., and Ogawa, Seishi

Published
2022
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3. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation

Author

Yoshizato, Tetsuichi, Nannya, Yasuhito, Atsuta, Yoshiko, Shiozawa, Yusuke, Iijima-Yamashita, Yuka, Yoshida, Kenichi, Shiraishi, Yuichi, Suzuki, Hiromichi, Nagata, Yasunobu, Sato, Yusuke, Kakiuchi, Nobuyuki, Matsuo, Keitaro, Onizuka, Makoto, Kataoka, Keisuke, Chiba, Kenichi, Tanaka, Hiroko, Ueno, Hiroo, Nakagawa, Masahiro M., Przychodzen, Bartlomiej, Haferlach, Claudia, Kern, Wolfgang, Aoki, Kosuke, Itonaga, Hidehiro, Kanda, Yoshinobu, Sekeres, Mikkael A., Maciejewski, Jaroslaw P., Haferlach, Torsten, Miyazaki, Yasushi, Horibe, Keizo, Sanada, Masashi, Miyano, Satoru, Makishima, Hideki, and Ogawa, Seishi

Published
2017
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4. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms

Author

Makishima, Hideki, primary, Saiki, Ryunosuke, additional, Nannya, Yasuhito, additional, Korotev, Sophia, additional, Gurnari, Carmelo, additional, Takeda, June, additional, Momozawa, Yukihide, additional, Best, Steve, additional, Krishnamurthy, Pramila, additional, Yoshizato, Tetsuichi, additional, Atsuta, Yoshiko, additional, Shiozawa, Yusuke, additional, Iijima-Yamashita, Yuka, additional, Yoshida, Kenichi, additional, Shiraishi, Yuichi, additional, Nagata, Yasunobu, additional, Kakiuchi, Nobuyuki, additional, Onizuka, Makoto, additional, Chiba, Kenichi, additional, Tanaka, Hiroko, additional, Kon, Ayana, additional, Ochi, Yotaro, additional, Nakagawa, Masahiro M., additional, Okuda, Rurika, additional, Mori, Takuto, additional, Yoda, Akinori, additional, Itonaga, Hidehiro, additional, Miyazaki, Yasushi, additional, Sanada, Masashi, additional, Ishikawa, Takayuki, additional, Chiba, Shigeru, additional, Tsurumi, Hisashi, additional, Kasahara, Senji, additional, Müller-Tidow, Carsten, additional, Takaori-Kondo, Akifumi, additional, Ohyashiki, Kazuma, additional, Kiguchi, Toru, additional, Matsuda, Fumihiko, additional, Jansen, Joop H., additional, Polprasert, Chantana, additional, Blombery, Piers, additional, Kamatani, Yoichiro, additional, Miyano, Satoru, additional, Malcovati, Luca, additional, Haferlach, Torsten, additional, Kubo, Michiaki, additional, Cazzola, Mario, additional, Kulasekararaj, Austin G., additional, Godley, Lucy A., additional, Maciejewski, Jaroslaw P., additional, and Ogawa, Seishi, additional

Published
2023
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5. Cooperative Effects of SRSF2 and STAG2 mutations on Development of Myelodysplastic Syndrome and Its Related Disorders

Author

Mori, Takuto, primary, Ochi, Yotaro, additional, Kon, Ayana, additional, Yoshizato, Tetsuichi, additional, Koseki, Haruhiko, additional, Nakayama, Manabu, additional, Yoda, Akinori, additional, Nakagawa, Masahiro Marshall, additional, Takeda, June, additional, Saiki, Ryunosuke, additional, Okuda, Rurika, additional, Nagata, Yasunobu, additional, Yoshida, Kenichi, additional, Sanada, Masashi, additional, Makishima, Hideki, additional, Takaori-Kondo, Akifumi, additional, Maciejewski, Jaroslaw P., additional, Atsuta, Yoshiko, additional, Haferlach, Torsten, additional, Nannya, Yasuhito, additional, and Ogawa, Seishi, additional

Published
2022
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6. Germline Risks and Clinical Impacts of DDX41 Mutations in Myeloid Malignancies

Author

Makishima, Hideki, primary, Saiki, Ryunosuke, additional, Nannya, Yasuhito, additional, Korotev, Sophia C., additional, Gurnari, Carmelo, additional, Takeda, June, additional, Momozawa, Yukihide, additional, Best, Steve, additional, Krishnamurthy, Pramila, additional, Yoshizato, Tetsuichi, additional, Atsuta, Yoshiko, additional, Shiozawa, Yusuke, additional, Iijima-Yamashita, Yuka, additional, Yoshida, Kenichi, additional, Shiraishi, Yuichi, additional, Nagata, Yasunobu, additional, Kakiuchi, Nobuyuki, additional, Onizuka, Makoto, additional, Chiba, Kenichi, additional, Tanaka, Hiroko, additional, Kon, Ayana, additional, Ochi, Yotaro, additional, Nakagawa, Masahiro Marshall, additional, Okuda, Rurika, additional, Mori, Takuto, additional, Yoda, Akinori, additional, Itonaga, Hidehiro, additional, Miyazaki, Yasushi, additional, Sanada, Masashi, additional, Ishikawa, Takayuki, additional, Chiba, Shigeru, additional, Tsurumi, Hisashi, additional, Kasahara, Senji, additional, Müller-Tidow, Carsten, additional, Takaori-Kondo, Akifumi, additional, Ohyashiki, Kazuma, additional, Kiguchi, Toru, additional, Matsuda, Fumihiko, additional, Jansen, Joop H., additional, Polprasert, Chantana, additional, Blombery, Piers, additional, Kamatani, Yoichiro, additional, Miyano, Satoru, additional, Malcovati, Luca, additional, Haferlach, Torsten, additional, Kubo, Michiaki, additional, Cazzola, Mario, additional, Kulasekararaj, Austin, additional, Godley, Lucy A., additional, Maciejewski, Jaroslaw P., additional, and Ogawa, Seishi, additional

Published
2022
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7. Long-Term Clonal Inversion in an MDS-RS Case with Dual SF3B1 Mutations

Author

Moura, Pedro Luis, primary, Hofman, Isabel Juliana F, additional, Nannya, Yasuhito, additional, Aliouat, Affaf, additional, Mortera-Blanco, Teresa, additional, Yoshizato, Tetsuichi, additional, Saiki, Ryunosuke, additional, Nakagawa, Masahiro Marshall, additional, Björklund, Ann-Charlotte, additional, Walldin, Gunilla, additional, Barbosa, Indira, additional, Jansson, Monika, additional, Grasso, Francesca, additional, Creignou, Maria, additional, Elvarsdottir, Edda Maria, additional, Woll, Petter S, additional, Jacobsen, Sten Eirik Waelgaard, additional, Ogawa, Seishi, additional, and Hellström-Lindberg, Eva, additional

Published
2022
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8. Distinct Pathogenesis of Clonal Hematopoiesis Revealed By Single Cell RNA Sequencing Integrated with Highly Sensitive Genotyping Method

Author

Nakagawa, Masahiro Marshall, primary, Inagaki, Ryosaku, additional, Kuroda, Yutaka, additional, Nannya, Yasuhito, additional, Zhao, Lanying, additional, Ochi, Yotaro, additional, Takeda, June, additional, Xingxing, Qi, additional, Yoda, Akinori, additional, Kon, Ayana, additional, Kakiuchi, Nobuyuki, additional, Makishima, Hideki, additional, Matsuda, Shuichi, additional, and Ogawa, Seishi, additional

Published
2022
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11. Distinct Pathogenesis of Clonal Hematopoiesis Revealed By Single Cell RNA Sequencing Integrated with Highly Sensitive Genotyping Method

Author

Nakagawa, Masahiro Marshall, primary, Inagaki, Ryosaku, additional, Kuroda, Yutaka, additional, Nannya, Yasuhito, additional, Zhao, Lanying, additional, Ochi, Yotaro, additional, Takeda, June, additional, Xingxing, Qi, additional, Yoda, Akinori, additional, Kon, Ayana, additional, Kakiuchi, Nobuyuki, additional, Makishima, Hideki, additional, Matsuda, Shuichi, additional, and Ogawa, Seishi, additional

Published
2021
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13. EPOR/JAK/STAT Signaling Pathway As Therapeutic Target of Acute Erythroid Leukemia

Author

Takeda, June, primary, Yoshida, Kenichi, additional, Nakagawa, Masahiro Marshall, additional, Nannya, Yasuhito, additional, Yoda, Akinori, additional, Morishita, Daisuke, additional, Saiki, Ryunosuke, additional, Chiba, Kenichi, additional, Tanaka, Hiroko, additional, Shiraishi, Yuichi, additional, Kuo, Ming-Chung, additional, Kerr, Cassandra M, additional, Nagata, Yasunobu, additional, Hiramoto, Nobuhiro, additional, Hangaishi, Akira, additional, Nakazawa, Hideyuki, additional, Ishiyama, Ken, additional, Miyano, Satoru, additional, Chiba, Shigeru, additional, Miyazaki, Yasushi, additional, Kitano, Toshiyuki, additional, Usuki, Kensuke, additional, Sezaki, Nobuo, additional, Tsurumi, Hisashi, additional, Miyawaki, Shuichi, additional, Maciejewski, Jaroslaw P., additional, Ishikawa, Takayuki, additional, Ohyashiki, Kazuma, additional, Ganser, Arnold, additional, Heuser, Michael, additional, Thol, Felicitas, additional, Shih, Lee-Yung, additional, Takaori-Kondo, Akifumi, additional, Makishima, Hideki, additional, and Ogawa, Seishi, additional

Published
2021
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14. Germ line DDX41mutations define a unique subtype of myeloid neoplasms

Author

Makishima, Hideki, Saiki, Ryunosuke, Nannya, Yasuhito, Korotev, Sophia, Gurnari, Carmelo, Takeda, June, Momozawa, Yukihide, Best, Steve, Krishnamurthy, Pramila, Yoshizato, Tetsuichi, Atsuta, Yoshiko, Shiozawa, Yusuke, Iijima-Yamashita, Yuka, Yoshida, Kenichi, Shiraishi, Yuichi, Nagata, Yasunobu, Kakiuchi, Nobuyuki, Onizuka, Makoto, Chiba, Kenichi, Tanaka, Hiroko, Kon, Ayana, Ochi, Yotaro, Nakagawa, Masahiro M., Okuda, Rurika, Mori, Takuto, Yoda, Akinori, Itonaga, Hidehiro, Miyazaki, Yasushi, Sanada, Masashi, Ishikawa, Takayuki, Chiba, Shigeru, Tsurumi, Hisashi, Kasahara, Senji, Müller-Tidow, Carsten, Takaori-Kondo, Akifumi, Ohyashiki, Kazuma, Kiguchi, Toru, Matsuda, Fumihiko, Jansen, Joop H., Polprasert, Chantana, Blombery, Piers, Kamatani, Yoichiro, Miyano, Satoru, Malcovati, Luca, Haferlach, Torsten, Kubo, Michiaki, Cazzola, Mario, Kulasekararaj, Austin G., Godley, Lucy A., Maciejewski, Jaroslaw P., and Ogawa, Seishi

Abstract

•DDX41germ line mutations explain ∼80% of known germ line predisposition to MNs in adults, and the life-long risk was ∼50%.•DDX41-mutated MDS patients rapidly progressed to AML, which was however, confined to those having truncating variants.

Published
2023
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18. Distinct Pathogenesis of Clonal Hematopoiesis Revealed By Single Cell RNA Sequencing Integrated with Highly Sensitive Genotyping Method

Author

Nakagawa, Masahiro Marshall, primary, Inagaki, Ryosaku, additional, Kuroda, Yutaka, additional, Nannya, Yasuhito, additional, Zhao, Lanying, additional, Ochi, Yotaro, additional, Takeda, June, additional, Xingxing, Qi, additional, Yoda, Akinori, additional, Kon, Ayana, additional, Kakiuchi, Nobuyuki, additional, Makishima, Hideki, additional, Matsuda, Shuichi, additional, and Ogawa, Seishi, additional

Published
2020
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19. Genotype-Phenotype Relationships and Therapeutic Targets in Acute Erythroid Leukemia

Author

Takeda, June, primary, Yoshida, Kenichi, additional, Yoda, Akinori, additional, Shih, Lee-Yung, additional, Nannya, Yasuhito, additional, Ochi, Yotaro, additional, Kon, Ayana, additional, Chiba, Kenichi, additional, Shiraishi, Yuichi, additional, Shiozawa, Yusuke, additional, Yoshizato, Tetsuichi, additional, Kerr, Cassandra M, additional, Nagata, Yasunobu, additional, Kitano, Toshiyuki, additional, Hangaishi, Akira, additional, Ishiyama, Ken, additional, Tsurumi, Hisashi, additional, Miyazaki, Yasushi, additional, Hiramoto, Nobuhiro, additional, Ishikawa, Takayuki, additional, Nakagawa, Masahiro Marshall, additional, Takaori-Kondo, Akifumi, additional, Chiba, Shigeru, additional, Nakazawa, Hideyuki, additional, Kuo, Ming-Chung, additional, Kataoka, Keisuke, additional, Saiki, Ryunosuke, additional, Tanaka, Hiroko, additional, Usuki, Kensuke, additional, Miyawaki, Shuichi, additional, Miyano, Satoru, additional, Maciejewski, Jaroslaw P., additional, Ganser, Arnold, additional, Heuser, Michael, additional, Thol, Felicitas, additional, Makishima, Hideki, additional, and Ogawa, Seishi, additional

Published
2020
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20. Novel Molecular Pathogenesis and Therapeutic Target in Acute Erythroid Leukemia

Author

Takeda, June, primary, Yoshida, Kenichi, primary, Nannya, Yasuhito, primary, Shih, Lee-Yung, primary, Kon, Ayana, primary, Yoda, Akinori, primary, Ochi, Yotaro, primary, Shiozawa, Yusuke, primary, Yoshizato, Tetsuichi, primary, Kerr, Cassandra M, primary, Shiraishi, Yuichi, primary, Chiba, Kenichi, primary, Nagata, Yasunobu, primary, Hangaishi, Akira, primary, Kitano, Toshiyuki, primary, Ishiyama, Ken, primary, Tsurumi, Hisashi, primary, Miyazaki, Yasushi, primary, Hiramoto, Nobuhiro, primary, Ishikawa, Takayuki, primary, Takaori-Kondo, Akifumi, primary, Nakagawa, Masahiro, primary, Sanada, Masashi, primary, Nakazawa, Hideyuki, primary, Kataoka, Keisuke, primary, Saiki, Ryunosuke, primary, Tanaka, Hiroko, primary, Usuki, Kensuke, primary, Miyawaki, Shuichi, primary, Miyano, Satoru, primary, Ganser, Arnold, primary, Heuser, Michael, primary, Maciejewski, Jaroslaw P., primary, Thol, Felicitas, primary, Makishima, Hideki, primary, and Ogawa, Seishi, primary

Published
2019
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23. Germline Risks and Clinical Impacts of DDX41Mutations in Myeloid Malignancies

Author

Makishima, Hideki, Saiki, Ryunosuke, Nannya, Yasuhito, Korotev, Sophia C., Gurnari, Carmelo, Takeda, June, Momozawa, Yukihide, Best, Steve, Krishnamurthy, Pramila, Yoshizato, Tetsuichi, Atsuta, Yoshiko, Shiozawa, Yusuke, Iijima-Yamashita, Yuka, Yoshida, Kenichi, Shiraishi, Yuichi, Nagata, Yasunobu, Kakiuchi, Nobuyuki, Onizuka, Makoto, Chiba, Kenichi, Tanaka, Hiroko, Kon, Ayana, Ochi, Yotaro, Nakagawa, Masahiro Marshall, Okuda, Rurika, Mori, Takuto, Yoda, Akinori, Itonaga, Hidehiro, Miyazaki, Yasushi, Sanada, Masashi, Ishikawa, Takayuki, Chiba, Shigeru, Tsurumi, Hisashi, Kasahara, Senji, Müller-Tidow, Carsten, Takaori-Kondo, Akifumi, Ohyashiki, Kazuma, Kiguchi, Toru, Matsuda, Fumihiko, Jansen, Joop H., Polprasert, Chantana, Blombery, Piers, Kamatani, Yoichiro, Miyano, Satoru, Malcovati, Luca, Haferlach, Torsten, Kubo, Michiaki, Cazzola, Mario, Kulasekararaj, Austin, Godley, Lucy A., Maciejewski, Jaroslaw P., and Ogawa, Seishi

Published
2022
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24. Analysis of Clonal Evolution/Heterogeneity of MDS By Simultaneous Detection of Both Mutation and Gene Expression By Single Cell Sequencing

Author

Nakagawa, Masahiro Marshall, primary, Inagaki, Ryosaku, additional, Nannya, Yasuhito, additional, Zhao, Lanying, additional, Kuroda, Yutaka, additional, Takeda, June, additional, Qi, Xingxing, additional, Yoda, Akinori, additional, Kon, Ayana, additional, Tsurumi, Hisashi, additional, Makishima, Hideki, additional, Matsuda, Shuichi, additional, and Ogawa, Seishi, additional

Published
2018
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25. Novel and Significant Impact of Germline Variants Predisposed to Pathogenic Somatic Mutations and Loss of Heterozygosity (LOH) in Myelodysplastic Syndromes (MDS) and Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Author

Makishima, Hideki, primary, Yoshizato, Tetsuichi, additional, Nannya, Yasuhito, additional, Momozawa, Yasuhide, additional, Atsuta, Yoshiko, additional, Shiozawa, Yusuke, additional, Iijima-Yamashita, Yuka, additional, Yoshida, Kenichi, additional, Shiraishi, Yuichi, additional, Suzuki, Hiromichi, additional, Takeda, June, additional, Nagata, Yasunobu, additional, Sato, Yusuke, additional, Kakiuchi, Nobuyuki, additional, Onizuka, Makoto, additional, Kataoka, Keisuke, additional, Chiba, Kenichi, additional, Tanaka, Hiroko, additional, Ueno, Hiroo, additional, Nakagawa, Masahiro Marshall, additional, Itonaga, Hidehiro, additional, Kanda, Yoshinobu, additional, Miyazaki, Yasushi, additional, Horibe, Keizo, additional, Sanada, Masashi, additional, Kamatani, Yoichiro, additional, Kubo, Michiaki, additional, Miyano, Satoru, additional, and Ogawa, Seishi, additional

Published
2018
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26. DNA Methylation and Genetic Profiles in 320 Patients with Myelodysplastic Syndromes

Author

Morimoto, Suguru, primary, Makishima, Hideki, additional, Nagata, Yasunobu, additional, Nadarajah, Niroshan, additional, Baer, Constance, additional, Alpermann, Tamara, additional, Nagae, Genta, additional, Nannya, Yasuhito, additional, Miyazaki, Yasushi, additional, Yoshida, Kenichi, additional, Yoshizato, Tetsuichi, additional, Nakagawa, Masahiro Marshall, additional, Inagaki, Ryosaku, additional, Takeda, June, additional, Fujii, Yoichi, additional, Takeuchi, Yasuhide, additional, Ueno, Hiroo, additional, Shiraishi, Yuichi, additional, Chiba, Kenichi, additional, Tanaka, Hiroko, additional, Sanada, Masashi, additional, Miyano, Satoru, additional, Haferlach, Claudia, additional, Kern, Wolfgang, additional, Aburatani, Hiroyuki, additional, Haferlach, Torsten, additional, and Ogawa, Seishi, additional

Published
2018
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28. Genome-Wide Analysis of Non-Coding Alterations in Pan-Myeloid Cancers Using Whole Genome Sequencing

Author

Nannya, Yasuhito, primary, Yoshida, Kenichi, additional, Zhao, Lanying, additional, Takeda, June, additional, Ueno, Hiroo, additional, Yoshizato, Tetsuichi, additional, Yoda, Akinori, additional, Nakagawa, Masahiro, additional, Makishima, Hideki, additional, Tanaka, Hiroko, additional, Hiramoto, Nobuhiro, additional, Muto, Hideharu, additional, Fuji, Shigeo, additional, Polprasert, Chantana, additional, Damm, Frederik, additional, Usuki, Kensuke, additional, Taguchi, Masataka, additional, Chiba, Shigeru, additional, Miyawaki, Shuichi, additional, Shih, Lee-Yung, additional, Tsurumi, Hisashi, additional, Kasahara, Senji, additional, Malcovati, Luca, additional, Ishikawa, Takayuki, additional, Jansen, Joop H., additional, Miyazaki, Yasushi, additional, Miyano, Satoru, additional, Cazzola, Mario, additional, and Ogawa, Seishi, additional

Published
2018
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30. Stag2 regulates Hematopoietic Differentiation and Self-Renewal

Author

Ochi, Yotaro, primary, Kon, Ayana, additional, Yoshida, Kenichi, additional, Kataoka, Keisuke, additional, Nakagawa, Masahiro Marshall, additional, Makishima, Hideki, additional, Nakayama, Manabu, additional, Koseki, Haruhiko, additional, Takaori-Kondo, Akifumi, additional, and Ogawa, Seishi, additional

Published
2017
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31. Pathogenic Mechanisms of DDX41Mutations in the Development of Myeloid Malignancies

Author

Kon, Ayana, Nakagawa, Masahiro Marshall, Kataoka, Keisuke, Kakiuchi, Nobuyuki, Makishima, Hideki, Nakayama, Manabu, Koseki, Haruhiko, Nannya, Yasuhito, and Ogawa, Seishi

Abstract

DDX41is a newly identified leukemia predisposition gene encoding an RNA helicase, whose germline mutations are tightly associated with late-onset myeloid malignancies. Importantly, germline DDX41mutations were also found in as many as ~7 % of sporadic cases of high-risk MDS, conferring the largest germline risk for myeloid malignancies. In typical cases, a germline loss-of-function allele (most commonly p.A500fs or p.D140fs, depending on the ethnicity) is compounded by a somatic missense mutation affecting the helicase domain in the remaining allele (p.R525H). However, the molecular mechanism by which DDX41mutations lead to myeloid neoplasms have not fully been elucidated.

Published
2023
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32. Epigenetic Classification of Acute Myeloid Leukemia Revealed By Genome-Wide Chromatin Profiling

Author

Ochi, Yotaro, Nannya, Yasuhito, Liew-Littorin, Markus, Kasahara, Senji, Hiramoto, Nobuhiro, Kanemura, Nobuhiro, Sezaki, Nobuo, Sakurada, Maki, Iwasaki, Makoto, Kanda, Junya, Ueda, Yasunori, Yoshihara, Satoshi, Osterroos, Albin, Motomura, Masanori, Nakagawa, Masahiro Marshall, Saiki, Ryunosuke, Yoda, Akinori, Okuda, Rurika, Shiraishi, Yuichi, Ishikawa, Takayuki, Miyano, Satoru, Takaori-Kondo, Akifumi, Lehmann, Soren, and Ogawa, Seishi

Abstract

Background

Published
2023
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34. Cooperative Effects of SRSF2and STAG2mutations on Development of Myelodysplastic Syndrome and Its Related Disorders

Author

Mori, Takuto, Ochi, Yotaro, Kon, Ayana, Yoshizato, Tetsuichi, Koseki, Haruhiko, Nakayama, Manabu, Yoda, Akinori, Nakagawa, Masahiro Marshall, Takeda, June, Saiki, Ryunosuke, Okuda, Rurika, Nagata, Yasunobu, Yoshida, Kenichi, Sanada, Masashi, Makishima, Hideki, Takaori-Kondo, Akifumi, Maciejewski, Jaroslaw P., Atsuta, Yoshiko, Haferlach, Torsten, Nannya, Yasuhito, and Ogawa, Seishi

Published
2022
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35. Physiological Srsf2P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice

Author

Kon, Ayana, Yamazaki, Satoshi, Nannya, Yasuhito, Kataoka, Keisuke, Ota, Yasunori, Nakagawa, Masahiro Marshall, Yoshida, Kenichi, Shiozawa, Yusuke, Morita, Maiko, Yoshizato, Tetsuichi, Sanada, Masashi, Nakayama, Manabu, Koseki, Haruhiko, Nakauchi, Hiromitsu, and Ogawa, Seishi

Abstract

Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant Srsf2expression using newly generated Vav1-Cre–mediated conditional knockin mice. Mice carrying a heterozygous Srsf2P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings. Srsf2-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the Srsf2mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in Srsf2-mutated mice. RNA sequencing of the Srsf2-mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as Csf3r, Fyn, Gnas, Nsd1, Hnrnpa2b1, and Trp53bp1. Among the mutant Srsf2-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of cassette exons, which were caused by the altered consensus motifs for the recognition of exonic splicing enhancers. Our findings suggest that the mutant Srsf2leads to a compromised HSC function by causing abnormal RNA splicing and expression, contributing to the deregulated hematopoiesis that recapitulates the MDS phenotypes, possibly as a result of additional genetic and/or environmental insults.

Published
2018
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36. The Genetic Landscape Of FPD/AML Revealed CDC25C Mutation As a Driver That Promotes Malignant Transformation

Author

Yoshimi, Akihide, primary, Toya, Takashi, additional, Nakagawa, Masahiro, additional, Kawazu, Masahito, additional, Nannya, Yasuhito, additional, Ichikawa, Motoshi, additional, Arai, Shunya, additional, Harada, Hironori, additional, Usuki, Kensuke, additional, Hayashi, Yasuhide, additional, Ito, Etsuro, additional, Kirito, Keita, additional, Nakajima, Hideaki, additional, Mano, Hiroyuki, additional, and Kurokawa, Mineo, additional

Published
2013
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39. AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors

Author

Nakagawa, Masahiro, primary, Shimabe, Munetake, additional, Watanabe-Okochi, Naoko, additional, Arai, Shunya, additional, Yoshimi, Akihide, additional, Shinohara, Akihito, additional, Nishimoto, Nahoko, additional, Kataoka, Keisuke, additional, Sato, Tomohiko, additional, Kumano, Keiki, additional, Nannya, Yasuhito, additional, Ichikawa, Motoshi, additional, Imai, Yoichi, additional, and Kurokawa, Mineo, additional

Published
2011
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49. Functional Characterization of Compound DDX41Germline and Somatic R525H Mutations in the Development of Myeloid Malignancies

Author

Kon, Ayana, Nakagawa, Masahiro Marshall, Inagaki, Ryosaku, Kataoka, Keisuke, Makishima, Hideki, Ochi, Yotaro, Nakayama, Manabu, Koseki, Haruhiko, Nannya, Yasuhito, and Ogawa, Seishi

Abstract

DDX41is a newly identified leukemia predisposition gene encoding an RNA helicase, whose germline mutations are tightly associated with late-onset myeloid malignancies. Importantly, germline DDX41mutations were also found in as many as ~7 % of sporadic cases of high-risk MDS, conferring the largest germline risk for myeloid malignancies. In typical cases, a germline loss-of-function allele (most commonly p.A500fs or p.D140fs, depending on the ethnicity) is compounded by a somatic missense mutation affecting the helicase domain in the remaining allele (p.R525H). However, the molecular mechanism by which DDX41mutations lead to myeloid neoplasms have not been elucidated.

Published
2020
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