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Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia.


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.

SUBMITTER: Matsuo H 

PROVIDER: S-EPMC6234363 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Recurrent <i>CCND3</i> mutations in <i>MLL</i>-rearranged acute myeloid leukemia.

Matsuo Hidemasa H   Yoshida Kenichi K   Fukumura Kazutaka K   Nakatani Kana K   Noguchi Yuki Y   Takasaki Saho S   Noura Mina M   Shiozawa Yusuke Y   Shiraishi Yuichi Y   Chiba Kenichi K   Tanaka Hiroko H   Okada Ai A   Nannya Yasuhito Y   Takeda June J   Ueno Hiroo H   Shiba Norio N   Yamato Genki G   Handa Hiroshi H   Ono Yuichiro Y   Hiramoto Nobuhiro N   Ishikawa Takayuki T   Usuki Kensuke K   Ishiyama Ken K   Miyawaki Shuichi S   Itonaga Hidehiro H   Miyazaki Yasushi Y   Kawamura Machiko M   Yamaguchi Hiroki H   Kiyokawa Nobutaka N   Tomizawa Daisuke D   Taga Takashi T   Tawa Akio A   Hayashi Yasuhide Y   Mano Hiroyuki H   Miyano Satoru S   Kamikubo Yasuhiko Y   Ogawa Seishi S   Adachi Souichi S  

Blood advances 20181101 21


In acute myeloid leukemia (AML), <i>MLL</i> (<i>KMT2A</i>) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of <i>MLL</i>-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric <i>MLL</i>-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML sa  ...[more]

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