The landscape of somatic mutations in Down syndrome-related myeloid disorders

Kenichi Yoshida; Tsutomu Toki; Yusuke Okuno; Rika Kanezaki; Yuichi Shiraishi; Aiko Sato-Otsubo; Masashi Sanada; Myoung Ja Park; Kiminori Terui; Hiromichi Suzuki; Ayana Kon; Yasunobu Nagata; Yusuke Sato; Ru Nan Wang; Norio Shiba; Kenichi Chiba; Hiroko Tanaka; Asahito Hama; Hideki Muramatsu; Daisuke Hasegawa; Kazuhiro Nakamura; Hirokazu Kanegane; Keiko Tsukamoto; Souichi Adachi; Kiyoshi Kawakami; Koji Kato; Ryosei Nishimura; Shai Izraeli; Yasuhide Hayashi; Satoru Miyano; Seiji Kojima; Etsuro Ito; Seishi Ogawa

doi:10.1038/ng.2759

The landscape of somatic mutations in Down syndrome-related myeloid disorders

Kenichi Yoshida, Tsutomu Toki, Yusuke Okuno, Rika Kanezaki, Yuichi Shiraishi, Aiko Sato-Otsubo, Masashi Sanada, Myoung Ja Park, Kiminori Terui, Hiromichi Suzuki, Ayana Kon, Yasunobu Nagata, Yusuke Sato, Ru Nan Wang, Norio Shiba, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Hideki Muramatsu, Daisuke HasegawaKazuhiro Nakamura, Hirokazu Kanegane, Keiko Tsukamoto, Souichi Adachi, Kiyoshi Kawakami, Koji Kato, Ryosei Nishimura, Shai Izraeli, Yasuhide Hayashi, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa

Research output: Contribution to journal › Article › peer-review

259 Citations (Scopus)

Abstract

Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).

Original language	English
Pages (from-to)	1293-1301
Number of pages	9
Journal	Nature genetics
Volume	45
Issue number	11
DOIs	https://doi.org/10.1038/ng.2759
Publication status	Published - Nov 2013
Externally published	Yes

All Science Journal Classification (ASJC) codes

Genetics

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Yoshida, K., Toki, T., Okuno, Y., Kanezaki, R., Shiraishi, Y., Sato-Otsubo, A., Sanada, M., Park, M. J., Terui, K., Suzuki, H., Kon, A., Nagata, Y., Sato, Y., Wang, R. N., Shiba, N., Chiba, K., Tanaka, H., Hama, A., Muramatsu, H., ... Ogawa, S. (2013). The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nature genetics, 45(11), 1293-1301. https://doi.org/10.1038/ng.2759

Yoshida, K, Toki, T, Okuno, Y, Kanezaki, R, Shiraishi, Y, Sato-Otsubo, A, Sanada, M, Park, MJ, Terui, K, Suzuki, H, Kon, A, Nagata, Y, Sato, Y, Wang, RN, Shiba, N, Chiba, K, Tanaka, H, Hama, A, Muramatsu, H, Hasegawa, D, Nakamura, K, Kanegane, H, Tsukamoto, K, Adachi, S, Kawakami, K, Kato, K, Nishimura, R, Izraeli, S, Hayashi, Y, Miyano, S, Kojima, S, Ito, E & Ogawa, S 2013, 'The landscape of somatic mutations in Down syndrome-related myeloid disorders', Nature genetics, vol. 45, no. 11, pp. 1293-1301. https://doi.org/10.1038/ng.2759

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title = "The landscape of somatic mutations in Down syndrome-related myeloid disorders",

abstract = "Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).",

author = "Kenichi Yoshida and Tsutomu Toki and Yusuke Okuno and Rika Kanezaki and Yuichi Shiraishi and Aiko Sato-Otsubo and Masashi Sanada and Park, {Myoung Ja} and Kiminori Terui and Hiromichi Suzuki and Ayana Kon and Yasunobu Nagata and Yusuke Sato and Wang, {Ru Nan} and Norio Shiba and Kenichi Chiba and Hiroko Tanaka and Asahito Hama and Hideki Muramatsu and Daisuke Hasegawa and Kazuhiro Nakamura and Hirokazu Kanegane and Keiko Tsukamoto and Souichi Adachi and Kiyoshi Kawakami and Koji Kato and Ryosei Nishimura and Shai Izraeli and Yasuhide Hayashi and Satoru Miyano and Seiji Kojima and Etsuro Ito and Seishi Ogawa",

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AU - Yoshida, Kenichi

AU - Toki, Tsutomu

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AU - Kanezaki, Rika

AU - Shiraishi, Yuichi

AU - Sato-Otsubo, Aiko

AU - Sanada, Masashi

AU - Park, Myoung Ja

AU - Terui, Kiminori

AU - Suzuki, Hiromichi

AU - Kon, Ayana

AU - Nagata, Yasunobu

AU - Sato, Yusuke

AU - Wang, Ru Nan

AU - Shiba, Norio

AU - Chiba, Kenichi

AU - Tanaka, Hiroko

AU - Hama, Asahito

AU - Muramatsu, Hideki

AU - Hasegawa, Daisuke

AU - Nakamura, Kazuhiro

AU - Kanegane, Hirokazu

AU - Tsukamoto, Keiko

AU - Adachi, Souichi

AU - Kawakami, Kiyoshi

AU - Kato, Koji

AU - Nishimura, Ryosei

AU - Izraeli, Shai

AU - Hayashi, Yasuhide

AU - Miyano, Satoru

AU - Kojima, Seiji

AU - Ito, Etsuro

AU - Ogawa, Seishi

PY - 2013/11

Y1 - 2013/11

N2 - Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).

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ER -

The landscape of somatic mutations in Down syndrome-related myeloid disorders

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