title: MEF2D-BCL9 Fusion Gene Is Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents.
abstract: Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis.
  
  
  
  We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients' leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles. On the basis of results obtained by RNA-seq, we performed genetic validation, functional analysis, and in vitro drug sensitivity testing using patients' samples and an exogenous expression model.
  
  
  
  We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were nonrandom gene fusions already described in ALL, and four of the remaining seven involved identical combination of MEF2D and BCL9. All MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Using a primary culture of leukemic blasts from a patient, we identified several molecular targeted drugs that conferred inhibitory effects in vitro.
  
  
  
  A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting.
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Kyogo
authors: K
authors: Suzuki
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Yusuke
authors: Y
authors: Okuno
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Nozomu
authors: N
authors: Kawashima
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Hideki
authors: H
authors: Muramatsu
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Tatsuya
authors: T
authors: Okuno
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Xinan
authors: X
authors: Wang
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Shinsuke
authors: S
authors: Kataoka
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Yuko
authors: Y
authors: Sekiya
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Motoharu
authors: M
authors: Hamada
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Norihiro
authors: N
authors: Murakami
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Daiei
authors: D
authors: Kojima
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Kotaro
authors: K
authors: Narita
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Atsushi
authors: A
authors: Narita
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Hirotoshi
authors: H
authors: Sakaguchi
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Kimiyoshi
authors: K
authors: Sakaguchi
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Nao
authors: N
authors: Yoshida
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Nobuhiro
authors: N
authors: Nishio
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Asahito
authors: A
authors: Hama
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Yoshiyuki
authors: Y
authors: Takahashi
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Kazuko
authors: K
authors: Kudo
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan.
authors: Koji
authors: K
authors: Kato
authors: Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima, Nagoya University Graduate School of Medicine; Yusuke Okuno and Nobuhiro Nishio, Nagoya University Hospital; Kotaro Narita, Hirotoshi Sakaguchi, Nao Yoshida, and Koji Kato, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya; Kimiyoshi Sakaguchi, Hamamatsu University School of Medicine, Hamamatsu; and Kazuko Kudo, Fujita Health University School of Medicine, Toyoake, Japan. kojimas@med.nagoya-u.ac.jp.
authors: Seiji
authors: S
authors: Kojima
mesh_terms: D000293:Adolescent; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007223:Infant; D064326:MEF2 Transcription Factors / Q000235:genetics; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D017423:Sequence Analysis, RNA; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: C111180:BCL9 protein, human; D006877:Hydroxamic Acids; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D014157:Transcription Factors; D000077337:Vorinostat; D000069286:Bortezomib; D003907:Dexamethasone; C486544:HDAC9 protein, human; D006655:Histone Deacetylases