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Title: Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia
Authors: Matsuo, Hidemasa  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-7578-006X (unconfirmed)
Yoshida, Kenichi
Fukumura, Kazutaka
Nakatani, Kana
Noguchi, Yuki
Takasaki, Saho
Noura, Mina
Shiozawa, Yusuke
Shiraishi, Yuichi
Chiba, Kenichi
Tanaka, Hiroko
Okada, Ai
Nannya, Yasuhito
Takeda, June
Ueno, Hiroo
Shiba, Norio
Yamato, Genki
Handa, Hiroshi
Ono, Yuichiro
Hiramoto, Nobuhiro
Ishikawa, Takayuki
Usuki, Kensuke
Ishiyama, Ken
Miyawaki, Shuichi
Itonaga, Hidehiro
Miyazaki, Yasushi
Kawamura, Machiko
Yamaguchi, Hiroki
Kiyokawa, Nobutaka
Tomizawa, Daisuke
Taga, Takashi
Tawa, Akio
Hayashi, Yasuhide
Mano, Hiroyuki
Miyano, Satoru
Kamikubo, Yasuhiko
Ogawa, Seishi  kyouindb  KAKEN_id
Adachi, Souichi
Author's alias: 松尾, 英将
吉田, 健一
福村, 知隆
中谷, 香菜
野口, 勇貴
高崎, 作歩
能浦, 三奈
塩澤, 裕介
白石, 友一
千葉, 健一
田中, 洋子
岡田, 愛
南谷, 泰仁
竹田, 淳恵
上野, 浩生
柴, 徳生
大和, 玄季
半田, 寛
小野, 祐一郎
平本, 展大
石川, 隆之
臼杵, 憲祐
石山, 謙
宮脇, 修一
糸永, 英弘
宮崎, 泰司
川村, 眞智子
山口, 博樹
清河, 信敬
富澤, 大輔
多賀, 崇
多和, 昭雄
林, 泰秀
間野, 博行
宮野, 悟
上久保, 靖彦
小川, 誠司
足立, 壯一
Issue Date: 13-Nov-2018
Publisher: American Society of Hematology
Journal title: Blood Advances
Volume: 2
Issue: 21
Start page: 2879
End page: 2889
Abstract: In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3–rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.
Description: 急性骨髄性白血病の新規遺伝子変異を発見 --乳がんの既存薬が治療に有効である可能性--. 京都大学プレスリリース. 2018-11-01.
Rights: © 2018 by The American Society of Hematology
URI: http://hdl.handle.net/2433/234946
DOI(Published Version): 10.1182/bloodadvances.2018019398
PubMed ID: 30381403
Related Link: http://www.kyoto-u.ac.jp/ja/research/research_results/2018/181101_1.html
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