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

Tokyo Children’s Cancer Study Group (TCCSG)

Research output: Contribution to journalArticle

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 m chain-pos-itive 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.

Original languageEnglish
Pages (from-to)128-137
Number of pages10
JournalHaematologica
Volume104
Issue number1
DOIs
Publication statusPublished - 01-01-2019

Fingerprint

B-Lymphoid Precursor Cells
Gene Fusion
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
CD5 Antigens
p16 Genes
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Recurrence
Salvage Therapy
Incidence
Gene Deletion
Stem Cell Transplantation
Transcriptome
Lymphoma
Up-Regulation
Down-Regulation
Steroids
Clinical Trials
Mutation

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

@article{ff0e9dbff23749df83d90a7cf93dd87c,
title = "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",
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 m chain-pos-itive 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.",
author = "{Tokyo Children’s Cancer Study Group (TCCSG)} and Kentaro Ohki and Nobutaka Kiyokawa and Yuya Saito and Shinsuke Hirabayashi and Kazuhiko Nakabayashi and Hitoshi Ichikawa and Yukihide Momozawa and Kohji Okamura and Ai Yoshimi and Hiroko Ogata-Kawata and Hiromi Sakamoto and Motohiro Kato and Keitaro Fukushima and Daisuke Hasegawa and Hiroko Fukushima and Masako Imai and Ryosuke Kajiwara and Takashi Koike and Isao Komori and Atsushi Matsui and Makiko Mori and Koichi Moriwaki and Yasushi Noguchi and Park, {Myoung Ja} and Takahiro Ueda and Shohei Yamamoto and Koichi Matsuda and Teruhiko Yoshida and Kenji Matsumoto and Kenichiro Hata and Michiaki Kubo and Yoichi Matsubara and Michiaki Kubo and Takashi Fukushima and Yasuhide Hayashi and Katsuyoshi Koh and Atsushi Manabe and Akira Ohara",
year = "2019",
month = "1",
day = "1",
doi = "10.3324/haematol.2017.186320",
language = "English",
volume = "104",
pages = "128--137",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Ferrata Storti Foundation",
number = "1",

}

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. / Tokyo Children’s Cancer Study Group (TCCSG).

In: Haematologica, Vol. 104, No. 1, 01.01.2019, p. 128-137.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Tokyo Children’s Cancer Study Group (TCCSG)

AU - Ohki, Kentaro

AU - Kiyokawa, Nobutaka

AU - Saito, Yuya

AU - Hirabayashi, Shinsuke

AU - Nakabayashi, Kazuhiko

AU - Ichikawa, Hitoshi

AU - Momozawa, Yukihide

AU - Okamura, Kohji

AU - Yoshimi, Ai

AU - Ogata-Kawata, Hiroko

AU - Sakamoto, Hiromi

AU - Kato, Motohiro

AU - Fukushima, Keitaro

AU - Hasegawa, Daisuke

AU - Fukushima, Hiroko

AU - Imai, Masako

AU - Kajiwara, Ryosuke

AU - Koike, Takashi

AU - Komori, Isao

AU - Matsui, Atsushi

AU - Mori, Makiko

AU - Moriwaki, Koichi

AU - Noguchi, Yasushi

AU - Park, Myoung Ja

AU - Ueda, Takahiro

AU - Yamamoto, Shohei

AU - Matsuda, Koichi

AU - Yoshida, Teruhiko

AU - Matsumoto, Kenji

AU - Hata, Kenichiro

AU - Kubo, Michiaki

AU - Matsubara, Yoichi

AU - Kubo, Michiaki

AU - Fukushima, Takashi

AU - Hayashi, Yasuhide

AU - Koh, Katsuyoshi

AU - Manabe, Atsushi

AU - Ohara, Akira

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 m chain-pos-itive 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.

AB - 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 m chain-pos-itive 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.

UR - http://www.scopus.com/inward/record.url?scp=85059248589&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059248589&partnerID=8YFLogxK

U2 - 10.3324/haematol.2017.186320

DO - 10.3324/haematol.2017.186320

M3 - Article

VL - 104

SP - 128

EP - 137

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 1

ER -