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Blood Adv. 2018 Nov 13;2(21):2879-2889. doi: 10.1182/bloodadvances.2018019398.

Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia.

Author information

1
Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2
Department of Clinical Laboratory, Kyoto University Hospital, Kyoto, Japan.
3
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
4
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5
Department of Cellular Signaling, Graduate School of Medicine.
6
Department of Pediatrics, and.
7
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
8
Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
9
Department of Pediatrics, Yokohama City University Hospital, Graduate School of Medicine, Yokohama, Japan.
10
Department of Pediatrics and.
11
Department of Hematology, Gunma University Graduate School of Medicine, Gunma, Japan.
12
Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
13
Department of Hematology, NTT Medical Center, Tokyo, Japan.
14
Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
15
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
16
Department of Hematology, Saitama Cancer Center, Saitama, Japan.
17
Department of Hematology, Nippon Medical School, Tokyo, Japan.
18
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
19
Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
20
Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan.
21
Department of Pediatrics, Osaka National Hospital, Osaka, Japan; and.
22
Japanese Red Cross Gunma Blood Center, Gunma, Japan.

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.

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