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Haematologica. 2019 Jan;104(1):128-137. doi: 10.3324/haematol.2017.186320. Epub 2018 Aug 31.

Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion.

Author information

1
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo oki-kn@ncchd.go.jp.
2
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo.
3
Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Fuchu-shi.
4
Department of Pediatrics, St. Luke's International Hospital, Chuo-ku, Tokyo.
5
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo.
6
Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Chuo-ku, Tokyo.
7
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama-shi, Kanagawa.
8
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo.
9
Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito-shi.
10
Department of Pediatrics, Dokkyo Medical University, Tochigi.
11
Department of Pediatrics, University of Tsukuba Hospital, Ibaraki.
12
Department of Pediatrics, Japanese Red Cross Musashino Hospital, Tokyo.
13
Department of Pediatrics, Yokohama City University Hospital, Kanagawa.
14
Department of Pediatrics, Tokai University School of Medicine, Kanagawa.
15
Department of Pediatrics, Matsudo City Hospital, Chiba.
16
Department of Pediatrics, Japanese Red Cross Maebashi Hospital, Gunma.
17
Department of Hematology/Oncology, Saitama Children's Medical Center.
18
Department of Pediatrics, Saitama Medical Center, Saitama Medical University.
19
Department of Pediatrics, Japanese Red Cross Narita Hospital, Chiba.
20
Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa-shi.
21
Department of Pediatrics, Nippon Medical School, Bunkyo-ku, Tokyo.
22
Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama-shi, Kanagawa.
23
Laboratory of Clinical Genome Sequencing Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku.
24
Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo.
25
Director, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo.
26
Department of Pediatrics, Toho University Omori Medical Center, Tokyo.
27
Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki.
28
Institute of Physiology and Medicine, Jobu University, Takasaki-shi, Gunma, Japan.

Abstract

Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic μ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.

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