Basic helix-loop-helix proteins E2A and HEB induce immature T-cell receptor rearrangements in nonlymphoid cells

Langerak, Anton W.; Wolvers-Tettero, I. L. M.; Gastel-Mol, Ellen J. van; Oud, Monique E.C.M.; Dongen, Jacques J. M. van

doi:10.1182/blood.v98.8.2456

Cited by 61 publications

(47 citation statements)

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“…Experiments on transfected nonlymphoid cells have shown that both V␦2-D␦3 and D␦2-D␦3 could be enforced by introducing RAG1 plus RAG2 plus a member of the E-protein family (E2-2, E2A, or HEB). The same transfections were unable to enforce any rearrangement to the J loci (6). Thus, the rearrangements of the V and D loci appear to be under loose control compared with the regulation of the complete V(D)J rearrangement.…”

Section: Discussionmentioning

confidence: 99%

“…Forward primers V␦2-5Ј and D␦2-5Ј as previously described (8) were placed in TCR␦V2 exon and in TCR ␦ intronic sequence preceding D␦2 segment, respectively. Reverse primer RDD3-cons4 and hydrolyzation probe T-D␦3-cons2 labeled with fluorescein and N,N,N,NЈ-tetramethyl-6-carboxyrhodamine placed in TCR␦D3 exon and adjacent intron sequence were previously described (6). Reverse primer R-JD␦1-cons1 and probe T-J␦1-cons1 used for amplification of V␦2-D␦-J␦1 complete rearrangement were placed in TCR ␦ J1 exon and 3Ј adjacent intronic sequence (van Dongen et al, unpublished observations and Fig.…”

Section: Methodsmentioning

confidence: 99%

“…In leukemias, the most frequent among the known cross-lineage TCR gene rearrangements are V␦2-D␦3 and D␦2-D␦3 of the TCR ␦ gene locus, which physiologically codes for TCR ␦-chain (5). Both V␦2-D␦3 and D␦2-D␦3 (occurring in 67% and 13% of precursor B ALL cases, respectively) represent incomplete TCR ␦ gene rearrangements, because J␦ loci are only rarely involved (6).…”

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confidence: 99%

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Cutting Edge: TCR δ Gene Is Frequently Rearranged in Adult B Lymphocytes

Krejčí

Prouzová

Horváth

et al. 2003

The Journal of Immunology

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TCR gene rearrangement generates diversity of T lymphocytes by V(D)J recombination. Ig genes are rearranged in B cells using the same enzyme machinery. Physiologically, TCR gene is postulated to rearrange exclusively in T lineage, but malignant B precursor lymphoblasts contain rearranged TCR genes in most patients. Several mechanisms by which malignant cells break the regulation of V(D)J recombination have been proposed. In this study we show that incomplete TCR δ rearrangements V2-D3 and D2-D3 occur each in up to 16% alleles in B lymphocytes of all healthy donors studied, but complete VDJ rearrangement was negative at the sensitivity limit of 1%. Data are based on real-time quantitative PCR validated by PAGE and sequencing of the cloned products. Therefore, TCR genes rearrange not exclusively in T lineage. This study opens up further questions regarding the exact extent of the “cross-lineage” TCR or Ig rearrangements in normal lymphocytes, specific subsets in which the cross-lineage rearrangements occur, and the physiological importance of these rearrangements.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cutting Edge: TCR δ Gene Is Frequently Rearranged in Adult B Lymphocytes

Krejčí

Prouzová

Horváth

et al. 2003

The Journal of Immunology

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“…18,19. Quantification of clone-specific antigen-specific receptor gene rearrangements was performed using germline probes and reverse primers [29][30][31][32][33] as described previously. 13 The albumin gene was used to normalize DNA concentration and quality.…”

Section: Ig/tcr Detectionmentioning

confidence: 99%

Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

et al. 2009

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Minimal residual disease (MRD) monitoring is an essential tool for risk group stratification in current treatment protocols for childhood acute lymphoblastic leukaemia (ALL). Although quantitative detection of clonal immunoglobulin (Ig) and T-cell receptor (TCR ) gene rearrangements is currently considered to be the standard method, leukaemia fusion genes provide other possible targets for MRD follow-up, as already demonstrated in TEL/AML1-positive ALLs. We analysed and compared MRD levels quantified by BCR/ABL transcript detection and by the standard Ig/TCR-based method in 218 bone marrow specimens from 17 children with BCR/ABL-positive ALL. We found only a limited overall correlation of MRD levels as assessed by the two methods (correlation coefficient R 2 ¼ 0.64). The correlation varied among patients from excellent (R 2 ¼ 0.99) to very poor (R 2 ¼ 0.17). Despite identical sensitivity of the approaches, 20% of the samples were negative by the Ig/TCR approach whereas positive by the BCR/ABL method. We show that multilineage involvement is at least partly responsible for the discrepancy. Moreover, our data demonstrate that BCR/ABL monitoring enables better and earlier prediction of relapse compared to the standard Ig/TCR methodology. We conclude that BCR/ABLbased MRD monitoring of childhood ALL is a clinically relevant tool and should be performed in parallel with the standard Ig/ TCR follow-up.

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“…Family-specific reverse primers and probes for immunoglobulin heavy chain, immunoglobulin light chain k, T-cell receptor d and T-cell receptor g were described previously. [18][19][20][21] Ig/TCR RQ-PCR was performed using the iCycler IQt real-time PCR Detection System (Bio-Rad, Hercules, CA, USA) and the ABI Prism 7700 real-time PCR System (Applied Biosystems, Foster City, CA, USA). Standard curves were prepared by diluting the diagnostic samples in polyclonal DNA from healthy donors.…”

Section: Detection Of Residual Diseasementioning

confidence: 99%

Minimal residual disease (MRD) analysis in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: is it possible to avoid MRD testing?

et al. 2008

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The ALL IC-BFM 2002 protocol was created as an alternative to the MRD-based AIEOP-BFM ALL 2000 study, to integrate early response criteria into risk-group stratification in countries not performing routine PCR-based MRD testing. ALL IC stratification comprises the response to prednisone, bone marrow (BM) morphology at days 15 and 33, age, WBC and BCR/ABL or MLL/ AF4 presence. Here, we compared this stratification to the MRDbased criteria using MRD evaluation in 163 patients from four ALL IC member countries at days 8, 15 and 33 and week 12. MRD negativity at day 33 was associated with an age of 1-5 years, WBCo20 000 ll À1 , non-T immunophenotype, good prednisone response and non-M3 morphology at day 15. There were no significant associations with gender or hyperdiploidy in the study group, or with TEL/AML1 fusion within BCP-ALL. Patients with M1/2 BM at day 8 tended to be MRD negative at week 12. Patients stratified into the standard-risk group had a better response than intermediate-risk group patients. However, 34% of them were MRD positive at day 33 and/or week 12. Our findings revealed that morphology-based ALL IC risk-group stratification allows the identification of most MRD high-risk patients, but fails to discriminate the MRD low-risk group assigned to therapy reduction.

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Basic helix-loop-helix proteins E2A and HEB induce immature T-cell receptor rearrangements in nonlymphoid cells

Cited by 61 publications

References 50 publications

Cutting Edge: TCR δ Gene Is Frequently Rearranged in Adult B Lymphocytes

Cutting Edge: TCR δ Gene Is Frequently Rearranged in Adult B Lymphocytes

Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

Minimal residual disease (MRD) analysis in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: is it possible to avoid MRD testing?

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