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Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia.
Matsuo, Hidemasa; 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; Adachi, Souichi.
Afiliação
  • Matsuo H; Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Yoshida K; Department of Clinical Laboratory, Kyoto University Hospital, Kyoto, Japan.
  • Fukumura K; Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
  • Nakatani K; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Noguchi Y; Department of Cellular Signaling, Graduate School of Medicine.
  • Takasaki S; Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Noura M; Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Shiozawa Y; Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Shiraishi Y; Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Chiba K; Department of Pediatrics, and.
  • Tanaka H; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Okada A; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Nannya Y; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Takeda J; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Ueno H; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Shiba N; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Yamato G; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Handa H; Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
  • Ono Y; Department of Pediatrics, Yokohama City University Hospital, Graduate School of Medicine, Yokohama, Japan.
  • Hiramoto N; Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
  • Ishikawa T; Department of Pediatrics and.
  • Usuki K; Department of Hematology, Gunma University Graduate School of Medicine, Gunma, Japan.
  • Ishiyama K; Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
  • Miyawaki S; Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
  • Itonaga H; Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
  • Miyazaki Y; Department of Hematology, NTT Medical Center, Tokyo, Japan.
  • Kawamura M; Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
  • Yamaguchi H; Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
  • Kiyokawa N; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
  • Tomizawa D; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
  • Taga T; Department of Hematology, Saitama Cancer Center, Saitama, Japan.
  • Tawa A; Department of Hematology, Nippon Medical School, Tokyo, Japan.
  • Hayashi Y; Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
  • Mano H; Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
  • Miyano S; Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan.
  • Kamikubo Y; Department of Pediatrics, Osaka National Hospital, Osaka, Japan; and.
  • Ogawa S; Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
  • Adachi S; Japanese Red Cross Gunma Blood Center, Gunma, Japan.
Blood Adv ; 2(21): 2879-2889, 2018 11 13.
Article em En | MEDLINE | ID: mdl-30381403
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Histona-Lisina N-Metiltransferase / Proteína de Leucina Linfoide-Mieloide / Ciclina D3 Tipo de estudo: Prognostic_studies Limite: Adolescent / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Histona-Lisina N-Metiltransferase / Proteína de Leucina Linfoide-Mieloide / Ciclina D3 Tipo de estudo: Prognostic_studies Limite: Adolescent / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Ano de publicação: 2018 Tipo de documento: Article