MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents

Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Kotaro Narita, Atsushi Narita, Hirotoshi Sakaguchi, Kimiyoshi Sakaguchi, Nao Yoshida, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, Kazuko KudoKoji Kato, Seiji Kojima

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Purpose: 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. Patients and Methods: 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. Results: We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were non-random 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)3451-3459
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number28
DOIs
Publication statusPublished - Oct 1 2016
Externally publishedYes

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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Gene Fusion
Precursor Cell Lymphoblastic Leukemia-Lymphoma
RNA Sequence Analysis
B-Lymphoid Precursor Cells
B-Cell Leukemia
Pediatrics
Transcriptome
Pharmaceutical Preparations
Dexamethasone
Neoplasms
Recurrence
Drug Therapy
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Suzuki, K., Okuno, Y., Kawashima, N., Muramatsu, H., Okuno, T., Wang, X., ... Kojima, S. (2016). MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents. Journal of Clinical Oncology, 34(28), 3451-3459. https://doi.org/10.1200/JCO.2016.66.5547

MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents. / Suzuki, Kyogo; Okuno, Yusuke; Kawashima, Nozomu; Muramatsu, Hideki; Okuno, Tatsuya; Wang, Xinan; Kataoka, Shinsuke; Sekiya, Yuko; Hamada, Motoharu; Murakami, Norihiro; Kojima, Daiei; Narita, Kotaro; Narita, Atsushi; Sakaguchi, Hirotoshi; Sakaguchi, Kimiyoshi; Yoshida, Nao; Nishio, Nobuhiro; Hama, Asahito; Takahashi, Yoshiyuki; Kudo, Kazuko; Kato, Koji; Kojima, Seiji.

In: Journal of Clinical Oncology, Vol. 34, No. 28, 01.10.2016, p. 3451-3459.

Research output: Contribution to journalArticle

Suzuki, K, Okuno, Y, Kawashima, N, Muramatsu, H, Okuno, T, Wang, X, Kataoka, S, Sekiya, Y, Hamada, M, Murakami, N, Kojima, D, Narita, K, Narita, A, Sakaguchi, H, Sakaguchi, K, Yoshida, N, Nishio, N, Hama, A, Takahashi, Y, Kudo, K, Kato, K & Kojima, S 2016, 'MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents', Journal of Clinical Oncology, vol. 34, no. 28, pp. 3451-3459. https://doi.org/10.1200/JCO.2016.66.5547
Suzuki, Kyogo ; Okuno, Yusuke ; Kawashima, Nozomu ; Muramatsu, Hideki ; Okuno, Tatsuya ; Wang, Xinan ; Kataoka, Shinsuke ; Sekiya, Yuko ; Hamada, Motoharu ; Murakami, Norihiro ; Kojima, Daiei ; Narita, Kotaro ; Narita, Atsushi ; Sakaguchi, Hirotoshi ; Sakaguchi, Kimiyoshi ; Yoshida, Nao ; Nishio, Nobuhiro ; Hama, Asahito ; Takahashi, Yoshiyuki ; Kudo, Kazuko ; Kato, Koji ; Kojima, Seiji. / MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 28. pp. 3451-3459.
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abstract = "Purpose: 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. Patients and Methods: 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. Results: We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were non-random 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. Conclusion: 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.",
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T1 - MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents

AU - Suzuki, Kyogo

AU - Okuno, Yusuke

AU - Kawashima, Nozomu

AU - Muramatsu, Hideki

AU - Okuno, Tatsuya

AU - Wang, Xinan

AU - Kataoka, Shinsuke

AU - Sekiya, Yuko

AU - Hamada, Motoharu

AU - Murakami, Norihiro

AU - Kojima, Daiei

AU - Narita, Kotaro

AU - Narita, Atsushi

AU - Sakaguchi, Hirotoshi

AU - Sakaguchi, Kimiyoshi

AU - Yoshida, Nao

AU - Nishio, Nobuhiro

AU - Hama, Asahito

AU - Takahashi, Yoshiyuki

AU - Kudo, Kazuko

AU - Kato, Koji

AU - Kojima, Seiji

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Purpose: 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. Patients and Methods: 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. Results: We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were non-random 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. Conclusion: 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.

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