Establishment of a Novel Cell Line (TS-2) of Pre-B Acute Lymphoblastic Leukemia with a t(1;19) Not Involving the E2A Gene

Yoshinari, Miyako; Imaizumi, Masue; Eguchi, Mariko; Ogasawara, Masahito; Saito, Toshiaki; Suzuki, Hoshiro; Koizumi, Yoshitsugu; Cui, Yan; Satō, Atsushi; Saisho, Takako; Ichinohasama, Ryo; Matsubara, Yoichi; Kamada, Nanao; Iinuma, Kazuie

doi:10.1016/s0165-4608(97)00260-4

Cited by 12 publications

(8 citation statements)

References 21 publications

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“…We previously reported a cell line, TS-2, with a pre-B-cell phenotype; these cells carry t(1;19) but lack E2A rearrangements and do not express E2A-PBX1. 8) In the present study we performed molecular cytogenetic analysis to characterize this variant t(1;19), and successfully identified a novel chromosomal translocation involving MEF2D at 1q22 and DAZAP1 at 19p13.3.…”

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confidence: 93%

Identification of a novel fusion gene in a pre‐B acute lymphoblastic leukemia with t(1;19)(q23;p13)

et al. 2004

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The most common nonrandom translocation found among childhood pre-B acute lymphoblastic leukemias (ALL) is t(1;19)(q23;p13), which frequently results in fusion of E2A with PBX1. However, rare cases of childhood ALL and various other hematological diseases with t(1;19) lack the E2A-PBX1 fusion. Analyzing a cell line with pre-B-cell phenotype, TS-2, that carries t(1;19)(q23;p13) but lacks the E2A-PBX1 fusion, we successfully cloned the breakpoints, which fell within introns of MEF2D and DAZAP1. Both chimeric transcripts, MEF2D-DAZAP1 and DAZAP1-MEF2D, whose sequences indicated in-frame fusions between MEF2D and DAZAP1, were expressed in TS-2 cells and in bonemarrow cells of the patient from whom the TS-2 was established. MEF2D-DAZAP1 and DAZAP1-MEF2D proteins were both located in the nucleus, and MEF2D-DAZAP1 was able to form dimers with MEF2D and HDAC4. In addition, exogenous expression of MEF2D-DAZAP1 and DAZAP1-MEF2D promoted the growth of HeLa cells. Given the frequency of t(1;19) without the E2A-PBX1 fusion in hematological malignancies, we suggest that MEF2D/DAZAP1 rearrangements might be involved in the pathogenesis of those diseases. (Cancer Sci 2004; 95: 503-507) he most common type of childhood leukemia is acute lymphoblastic leukemia (ALL), which has a B-cell precursor phenotype.1) The main subtypes of ALL involve multiple genetic alterations including point mutations and deletions, and are also characterized by gross chromosomal changes such as translocations, which are likely to cause illegitimate recombination or juxtaposition of normally separated genes. In leukemias an in-frame fusion gene is often created, generating a hybrid protein with altered properties. Although more than 200 genes are known to be involved in translocations in leukemias, certain genes predominate in those events and the others are involved only rarely. 1)The most common nonrandom translocation in childhood pre-B ALL is t(1;19)(q23;p13), usually involving fusion between PBX1 at 1q23 and E2A at 19p13.3. The chimeric gene, E2A-PBX1, encodes a protein that contains the transactivation domain of E2A and the DNA-binding homeodomain of PBX1. 2)Although an identical E2A-PBX1 chimeric gene can be detected in more than 95% of ALL cases with t(1;19), in rare cases the E2A-PBX1 fusion gene is absent. 3,4)

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confidence: 93%

Identification of a novel fusion gene in a pre‐B acute lymphoblastic leukemia with t(1;19)(q23;p13)

et al. 2004

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“…9 The TS-2 cell line was established from childhood pre-B ALL 10 and carries t(1;19)(q23;p13) without the E2A gene rearrangement. REH, a t(12;21)-positive ALL cell line, 11 was used as a positive control for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for TEL-AML1 fusion transcript.…”

Section: Cell Linesmentioning

confidence: 99%

Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals

Eguchi‐Ishimae

Eguchi

Ishii

et al. 2001

Blood

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IntroductionThe t(12;21)(p13;q22) is one of the most common chromosome translocations in childhood acute lymphoblastic leukemia (ALL). [1][2][3] This translocation is associated with rearrangement of the TEL (ETV6) gene on chromosome 12 and the AML1(CBFA2) gene on chromosome 21 resulting in TEL-AML1 fusion. Although many studies on the TEL-AML1 fusion gene focused on the biologic significance of leukemogenesis, little is known about the mechanisms involved in the cleavage of TEL and AML1 and subsequent fusion of the TEL-AML1 gene. Chemotherapy-related secondary leukemia is frequently associated with rearrangement of the MLL(ALL1) gene. Several clinicoepidemiologic studies have indicated that topoisomerase-II (topo-II) inhibitors cause rearrangement of the MLL gene. 4 These findings are supported by in vitro studies that have demonstrated that MLL rearrangement could be induced by topo-II inhibitors in human hematopoietic cells. 5 Site-specific cleavage within the MLL gene can also be induced by nongenotoxic stimuli involved in apoptotic cell death, suggesting that this cleavage is not specific to topo-II inhibitors but is rather part of a chromatin fragmentation similar to the generalized cellular response to apoptotic stimuli. 6 Based on these early findings, we speculated that general apoptotic stimuli on hematopoietic cells could play a key role in chromosomal translocation involving not only MLL but also TEL, another gene frequently altered in hematopoietic malignancies. To investigate whether apoptotic stimuli could trigger a cascade of events that ultimately leads to the formation of the TEL-AML1 fusion gene, we studied the in vitro conditions inducing the formation of DNA double-strand break (DSB) ends within TEL and AML1 genes. Our study indicates that DSBs of TEL and AML1 can be induced by apoptotic stimuli and this DNA cleavage appears to be the first step in the generation of TEL-AML1 fusion in immature B lymphocytes, which is considered to be an early or initiating event in childhood ALL. 7,8 Materials and methods Cell linesRS4;11 is an ALL cell line and has MLL-AF4 fusion gene as result of t(4;11)(q21;q23). 9 The TS-2 cell line was established from childhood pre-B ALL 10 and carries t(1;19)(q23;p13) without the E2A gene rearrangement. REH, a t(12;21)-positive ALL cell line, 11 was used as a positive control for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for TEL-AML1 fusion transcript. Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (EB-LCLs) were established from peripheral blood lymphocytes infected with the EBV strain B95-8, as described previously. 12 Cell lines were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) at 37°C in 5% CO 2 in air. Peripheral blood and cord blood samplesPeripheral blood samples of nonleukemic individuals were obtained from outpatients consulting several hospitals during December 1997 to April 1998 with informed consent. These individuals had no history of hematopoietic malignancy or administration of an...

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“…TS-2 (kindly provided by Drs Yoshinari and Imaizumi, Tohoku University, Sendai, Japan) contains a t(1;19)(q23;p13), but lacks E2A gene rearrangements and E2A-PBX1 fusion transcripts. 25 Twentythree primary ALL patient samples that had been cryopreserved (for up to 12 years) or stored as archived fixed cell pellets were obtained from the leukemia cell bank of The Children's Hospital and The Colorado Genetics Laboratory, Denver, CO. Twenty-one of these samples were obtained at initial diagnosis, one at the time of induction failure (No. 3709), and one at first bone marrow relapse (No.…”

Section: Specimensmentioning

confidence: 99%

Detection of E2A translocations in leukemias via fluorescence in situ hybridization

et al. 2001

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Establishment of a Novel Cell Line (TS-2) of Pre-B Acute Lymphoblastic Leukemia with a t(1;19) Not Involving the E2A Gene

Cited by 12 publications

References 21 publications

Identification of a novel fusion gene in a pre‐B acute lymphoblastic leukemia with t(1;19)(q23;p13)

Identification of a novel fusion gene in a pre‐B acute lymphoblastic leukemia with t(1;19)(q23;p13)

Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals

Detection of E2A translocations in leukemias via fluorescence in situ hybridization

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