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

Ohki, Kentaro; Kiyokawa, Nobutaka; Saito, Yuya; Hirabayashi, Shinsuke; Nakabayashi, Kazuhiko; Ichikawa, Hitoshi; Momozawa, Yukihide; Okamura, Koji; Yoshimi, Ai; Ogata‐Kawata, Hiroko; Sanada, Hiromi; Kato, Motohiro; Fukushima, Keitaro; Hasegawa, Daisuke; Fukushima, Hiroko; Imai, Masako; Kajiwara, Ryosuke; Kitahara, Takashi; Komori, Isao; Matsui, Atsushi; Mori, Makiko; Moriwaki, Koichi; Noguchi, Yasushi; Park, Myoung-ja; Ueda, Takahiro; Yamamoto, Shohei; Matsuda, Koichi; Yoshida, Teruhiko; Matsumoto, Kenji; Hata, Kenichiro; Kubo, Michiaki; Matsubara, Yoichi; Takahashi, Hiroyuki; Fukushima, Takashi; Hayashi, Yasuhide; Koh, Katsuyoshi; Manabe, Atsushi; Ohara, Akira

doi:10.3324/haematol.2017.186320

Cited by 73 publications

(80 citation statements)

References 43 publications

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“…We conducted a randomized controlled trial comparing the efficacy of low-dose continuous cytarabine infusion with conventional cytarabine block in the consolidation phase in the SR/HR groups because of the excellent outcome reported for continuous cytarabine infusion in the OCLSG-94 trial 7 ; however, there was no significant difference in pEFS or pOS between the two arms. Recent studies have revealed that subtypes of B-ALL associated with poor prognosis, such as Ph-like ALL [16][17][18] , IKZF1plus ALL 19 , and MEF2D-rearranged ALL 20,21 , comprise a substantial proportion of B-ALL in the NCI-HR category. Consistent with these findings, we previously reported poor prognosis for patients with B-ALL with IKZF1 deletion in the JACLS ALL-02 study, particularly in NCI-HR or PPR patients 22,23 .…”

Section: Discussionmentioning

confidence: 99%

Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02

et al. 2020

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This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02.

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Section: Discussionmentioning

confidence: 99%

Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02

et al. 2020

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“…It should be noted that the karyotypes in our cell lines were highly biased in comparison with those in childhood BCP-ALL patients: 14 cell lines were BCR/ABL1-positive, 13 cell lines were TCF3/PBX1positive, 12 cell lines were MLL (KMT2A)-rearranged, and 3 cell lines were TCF3/HLF-positive. Furthermore, we later discovered that 15 cell lines were positive for MEF2D-fusions [18], which are recently identi ed fusion genes with a poor therapeutic outcome [19,20]. In contrast, only four cell lines were ETV6/RUNX1-positive, and no cell lines were hyperdiploid.…”

Section: Discussionmentioning

confidence: 99%

Association of relapse-linked ARID5B single nucleotide polymorphisms with drug resistance in B-cell precursor acute lymphoblastic leukemia cell lines

Tamai

Huang

Kagami

et al. 2020

Preprint

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Background The genetic variants of the ARID5B gene have recently been reported to be associated with disease susceptibility and treatment outcome in childhood acute lymphoblastic leukemia (ALL). However, few studies have explored the association of ARID5B with sensitivities to chemotherapeutic agents. Methods We genotyped susceptibility-linked rs7923074 and rs10821936 as well as relapse-linked rs4948488, rs2893881, and rs6479778 of ARDI5B by direct sequencing of polymerase chain reaction (PCR) products in 72 B-cell precursor-ALL (BCP-ALL) cell lines established from Japanese patients. We also quantified their ARID5B expression levels by real-time reverse transcription PCR, and determined their 50% inhibitory concentration (IC50) values by alamarBlue assays in nine representative chemotherapeutic agents used for ALL treatment. Results No significant associations were observed in genotypes of the susceptibility-linked single nucleotide polymorphisms (SNPs) and the relapsed-linked SNPs with ARID5B gene expression levels. Of note, IC50 values of vincristine (VCR) (median IC50: 39.6 ng/ml) in 12 cell lines with homozygous genotype of risk allele (C) in the relapse-linked rs4948488 were significantly higher (p=0.031 in Mann–Whitney U test) than those (1.04 ng/ml) in 60 cell lines with heterozygous or homozygous genotypes of the non-risk allele (T). Furthermore, the IC50 values of mafosfamide [Maf; active metabolite of cyclophosphamide (CY)] and cytarabine (AraC) tended to be associated with the genotype of rs4948488. Similar associations were observed in genotypes of the relapse-linked rs2893881 and rs6479778, but not in those of the susceptibility-linked rs7923074 and rs10821936. In addition, the IC50 values of methotrexate (MTX) were significantly higher (p=0.023) in 36 cell lines with lower ARID5B gene expression (median IC50: 37.1 ng/ml) than those in the other 36 cell lines with higher expression (16.9 ng/ml). Conclusion These observations in 72 BCP-ALL cell lines suggested that the risk allele of the relapse-linked SNPs of ARID5B may be involved in a higher relapse rate because of resistance to chemotherapeutic agents such as VCR, CY, and AraC. In addition, lower ARID5B gene expression may be associated with MTX resistance.

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“…STIL-TAL1 cannot be classified into any family. 4.5 Along with the MEF2D-FM, ZNF384-FM, and PAX5-FM, which were recently reported in the literature, 14,[31][32][33][34][35] most of the FGs in hematological malignancies discovered to date can be clustered into about 20 major FG-FMs (Table 1). Furthermore, the content of FGs that can be covered in these FG-FMs far exceeds the known FGs in de facto.…”

Section: Classification and Recognition Of Fgs As "Fusion Gene Family"mentioning

confidence: 91%

“…21,32 FGs involving MEF2D have recently been identified in B-ALL, and the incidence of MEF2D-FGs overall was 2.4% in consecutive B-ALL patients in a single clinical trial. 33,34 MEF2D-FGs-positive patients frequently presented a cytoplasmic µ chain-positive, pre-B immunophenotype and often expressed an aberrant CD5 antigen. Elevated GATA3 expression was also a characteristic feature of MEF2D-FGs-positive patients, and PHF6 mutations showed an unexpectedly high frequency (50%) in them.…”

Section: Technological Advances and New Discoveriesmentioning

confidence: 99%

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Advances in Fusion Gene Research and Fusion Gene Families in Hematological Malignancies

Chen

Wang

et al. 2019

Int J Med Rev

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Fusion genes (FGs) are major molecular biological abnormalities in hematological malignancies and have become well-established molecular markers for disease classification, risk stratification, and targeted therapies. The long tail phenomenon is observed in the distribution of FGs, which means that except for dozens of the most common FGs, the positive rates of the other FGs are all below 1%, even if they have been frequently reported in the literature. However, the total positive rate of these singly relatively rare FGs is actually not low due to their wide variety and numerous members. We therefore put forward the conception "fusion gene family, FG-FM" to describe fusions that share one common protagonist gene with different partner genes. Most of the FGs in hematological malignancies discovered to date can be classified into about 20 major families. Based on the characteristics of the currently reported FGs, it can be expected that although a great many FGs may be identified in the future, the total number of FG-FMs is rather limited. FGs in the same FG-FM often have similarities in pathogenicity, clinical features, and treatment outcomes. Classifying FGs according to FG-FMs will aid in understanding their pathogenicity and optimizing detection schemes.

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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

Cited by 73 publications

References 43 publications

Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02

Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02

Association of relapse-linked ARID5B single nucleotide polymorphisms with drug resistance in B-cell precursor acute lymphoblastic leukemia cell lines

Advances in Fusion Gene Research and Fusion Gene Families in Hematological Malignancies

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