MEF2D-BCL9 Fusion Gene Is Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents.

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 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.

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.

• Authors: 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 Kudo, Koji Kato, Seiji Kojima
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 34 Issue 28 Pg. 3451-9 (10 01 2016) ISSN: 1527-7755 [Electronic] United States
• PMID: 27507882 (Publication Type: Journal Article)
• Copyright: © 2016 by American Society of Clinical Oncology.

Chemical References

• BCL9 protein, human
• Hydroxamic Acids
• MEF2 Transcription Factors
• MEF2D protein, human
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• RNA, Neoplasm
• Repressor Proteins
• Transcription Factors
• Vorinostat
• Bortezomib
• Dexamethasone
• HDAC9 protein, human
• Histone Deacetylases

Topics

• Adolescent
• Bortezomib (pharmacology)
• Cell Line, Tumor
• Child
• Dexamethasone (pharmacology)
• Drug Screening Assays, Antitumor
• HEK293 Cells
• Histone Deacetylases (biosynthesis, genetics)
• Humans
• Hydroxamic Acids (pharmacology)
• Infant
• MEF2 Transcription Factors (genetics)
• Molecular Targeted Therapy
• Neoplasm Proteins (genetics)
• Oncogene Proteins, Fusion (genetics)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (blood, drug therapy, genetics, pathology)
• RNA, Neoplasm (genetics)
• Repressor Proteins (biosynthesis, genetics)
• Sequence Analysis, RNA
• Transcription Factors
• Tumor Cells, Cultured
• Vorinostat