The landscape of somatic mutations in Down syndrome-related myeloid disorders.
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%).
1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [3].
Kenichi
K
Yoshida
Tsutomu
T
Toki
Yusuke
Y
Okuno
Rika
R
Kanezaki
Yuichi
Y
Shiraishi
Aiko
A
Sato-Otsubo
Masashi
M
Sanada
Myoung-ja
MJ
Park
Kiminori
K
Terui
Hiromichi
H
Suzuki
Ayana
A
Kon
Yasunobu
Y
Nagata
Yusuke
Y
Sato
RuNan
R
Wang
Norio
N
Shiba
Kenichi
K
Chiba
Hiroko
H
Tanaka
Asahito
A
Hama
Hideki
H
Muramatsu
Daisuke
D
Hasegawa
Kazuhiro
K
Nakamura
Hirokazu
H
Kanegane
Keiko
K
Tsukamoto
Souichi
S
Adachi
Kiyoshi
K
Kawakami
Koji
K
Kato
Ryosei
R
Nishimura
Shai
S
Izraeli
Yasuhide
Y
Hayashi
Satoru
S
Miyano
Seiji
S
Kojima
Etsuro
E
Ito
Seishi
S
Ogawa
D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics* / Q000276:immunology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D050982:GATA1 Transcription Factor / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics*; D007955:Leukemoid Reaction / Q000235:genetics*; D022423:Myeloid Cells; D009196:Myeloproliferative Disorders / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D000097722:Cohesins
D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000071221:Enhancer of Zeste Homolog 2 Protein; D050982:GATA1 Transcription Factor; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2; D012097:Repressor Proteins; D000097722:Cohesins; C000619697:CTCF protein, human; C494688:GATA1 protein, human; C574033:NSL1 protein, human; C498409:EZH2 protein, human