Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia

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Presentation transcript:

Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia by Hidemasa Matsuo, Kenichi Yoshida, Kazutaka Fukumura, Kana Nakatani, Yuki Noguchi, Saho Takasaki, Mina Noura, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Ai Okada, Yasuhito Nannya, June Takeda, Hiroo Ueno, Norio Shiba, Genki Yamato, Hiroshi Handa, Yuichiro Ono, Nobuhiro Hiramoto, Takayuki Ishikawa, Kensuke Usuki, Ken Ishiyama, Shuichi Miyawaki, Hidehiro Itonaga, Yasushi Miyazaki, Machiko Kawamura, Hiroki Yamaguchi, Nobutaka Kiyokawa, Daisuke Tomizawa, Takashi Taga, Akio Tawa, Yasuhide Hayashi, Hiroyuki Mano, Satoru Miyano, Yasuhiko Kamikubo, Seishi Ogawa, and Souichi Adachi BloodAdv Volume 2(21):2879-2889 November 13, 2018 © 2018 by The American Society of Hematology

Hidemasa Matsuo et al. Blood Adv 2018;2:2879-2889 © 2018 by The American Society of Hematology

Mutational landscape of pediatric MLL-rearranged AML Mutational landscape of pediatric MLL-rearranged AML. Driver or recurrent mutations and copy-number alterations observed in pediatric MLL-rearranged AML (n = 56). Mutational landscape of pediatric MLL-rearranged AML. Driver or recurrent mutations and copy-number alterations observed in pediatric MLL-rearranged AML (n = 56). The frequencies of mutated genes are shown on the right. SNV, single-nucleotide variant; SV, structural variant. Hidemasa Matsuo et al. Blood Adv 2018;2:2879-2889 © 2018 by The American Society of Hematology

CCND3 mutations in MLL-rearranged AML and disease subtype–specific pattern of CCND1, CCND2, and CCND3 mutations and expression. CCND3 mutations in MLL-rearranged AML and disease subtype–specific pattern of CCND1, CCND2, and CCND3 mutations and expression. (A) Domain structure and location of CCND3 mutations in pediatric and adult MLL-rearranged AML. Lollipop plots were generated using ProteinPaint (https://pecan.stjude.org/proteinpaint/). (B) Mutations of CCND1, CCND2, and CCND3 in pediatric AML patients with t(8;21) and MLL rearrangements (MLL-r). (C) Messenger RNA expression levels of CCND1, CCND2, and CCND3 in t(8;21) AML (n = 60) and MLL-rearranged AML (n = 43). ***P < .001. Hidemasa Matsuo et al. Blood Adv 2018;2:2879-2889 © 2018 by The American Society of Hematology

Effects of CDK4/6 inhibitors in MLL-rearranged AML cell lines. Effects of CDK4/6 inhibitors in MLL-rearranged AML cell lines. (A) Cell proliferation assay. ML-2, MV4-11, MOLM-13, THP-1, and NOMO-1 cells were cultured in the presence of DMSO, palbociclib (500 nM), or abemaciclib (500 nM). (B) Cell-cycle analysis. Flow cytometric analysis of cell lines treated with DMSO, palbociclib (500 nM), or abemaciclib (500 nM) for 24 hours and stained with propidium iodide. (C) Comparison of percentages of G2/M and S phase cells. (D) Immunoblot analysis revealed significantly lower expression of cyclin D3 proteins in THP-1 cells transfected with siRNA against human cyclin D3 transcript (left column: siCCND3) than in THP-1 cells transfected with non-targeting siRNA (right column: siControl). (E-G) THP-1 cells transfected with siCCND3 showed significant impairment in cell proliferation (E) and cell-cycle progression from G1 to S phase (F-G) compared with those transfected with nontargeting siRNA. (H) Schematic figure showing that the cyclin D3-CDK4/6 complex promotes cell-cycle progression and CDK4/6 inhibitors are promising therapeutic agents in MLL-rearranged AML cells. Data are presented as the mean ± standard error of 3 independent experiments. ***P < .001, *P < .05. Hidemasa Matsuo et al. Blood Adv 2018;2:2879-2889 © 2018 by The American Society of Hematology

Prognostic significance of fusion partners in pediatric MLL-rearranged AML and coexisting mutations in pediatric MLL-MLLT3–rearranged AML. (A) Comparison of patient RFS and OS according to MLL fusion partner. Prognostic significance of fusion partners in pediatric MLL-rearranged AML and coexisting mutations in pediatric MLL-MLLT3–rearranged AML. (A) Comparison of patient RFS and OS according to MLL fusion partner. (B) Comparison of RFS and OS for patients with pediatric MLL-MLLT3–rearranged AML with and without coexisting mutations. Survival estimates were compared using the log-rank test. Hidemasa Matsuo et al. Blood Adv 2018;2:2879-2889 © 2018 by The American Society of Hematology