The landscape of somatic mutations in Down syndrome-related myeloid disorders - PubMed (original) (raw)

. 2013 Nov;45(11):1293-9.

doi: 10.1038/ng.2759. Epub 2013 Sep 22.

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, RuNan 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

Affiliations

• PMID: 24056718
• DOI: 10.1038/ng.2759

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

Kenichi Yoshida et al. Nat Genet. 2013 Nov.

Erratum in

• Nat Genet. 2013 Dec;45(12):1516

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%).

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