T-Cell Receptor Rearrangements Determined Using Fragment Analysis in Patients With T-Acute Lymphoblastic Leukemia
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Background: Chromosomal abnormalities and common genetic rearrangements related to T-acute lymphoblastic leukemia (T-ALL) are not clear. We investigated T-cell receptor (TCR) rearrangement in Korean T-ALL patients by fragment analysis, examining frequency, association between clinicopathologic characteristics and TCR clonality, and feasibility for detecting minimal residual disease (MRD). Methods: In 51 Korean patients diagnosed as having T-ALL, TCR rearrangement was analyzed using the IdentiClone TCR gene clonality assay (InVivoScribe Technologies, San Diego, CA, USA) from archived bone marrow specimens. Limit of detection (LOD) and clonal stability at relapse were evaluated. The association between clinical prognosis and TCR clonality was examind by age and immunophenotypic classification. Results: Thirty-eight patients (74.5%) had 62 clonal products of TCRβ, TCRγ, and/or TCRδ rearrangements at diagnosis. Children with T-ALL (<12 years) showed a higher frequency of clonality (93.8%) than adolescents/adults (65.7%; ≥12 years). Patients with a mature immunophenotype (84.4%) showed a relatively higher frequency of clonality than those with the immature immunophenotype (57.9%). Survival and event-free survival were not influenced by immunophenotype or TCR clonality. The LOD was 1%. Clonal evolution at the relapse period was noted. Conclusions: The overall detection rate of TCR clonality was 74.5%. Survival did not differ by TCR clonality or immunophenotype and age group. Fragment analysis of TCR rearrangement cannot be used to assess MRD due to low sensitivity. Further research on the relationship between prognosis and frequency of TCR rearrangements is needed, using more sensitive methods to detect clonality and monitor MRD.
Abstract
Background: Chromosomal abnormalities and common genetic rearrangements related to T-acute lymphoblastic leukemia (T-ALL) are not clear. We investigated T-cell receptor (TCR) rearrangement in Korean T-ALL patients by fragment analysis, examining frequency, association between clinicopathologic characteristics and TCR clonality, and feasibility for detecting minimal residual disease (MRD). Methods: In 51 Korean patients diagnosed as having T-ALL, TCR rearrangement was analyzed using the IdentiClone TCR gene clonality assay (InVivoScribe Technologies, San Diego, CA, USA) from archived bone marrow specimens. Limit of detection (LOD) and clonal stability at relapse were evaluated. The association between clinical prognosis and TCR clonality was examind by age and immunophenotypic classification. Results: Thirty-eight patients (74.5%) had 62 clonal products of TCRβ, TCRγ, and/or TCRδ rearrangements at diagnosis. Children with T-ALL (<12 years) showed a higher frequency of clonality (93.8%) than adolescents/adults (65.7%; ≥12 years). Patients with a mature immunophenotype (84.4%) showed a relatively higher frequency of clonality than those with the immature immunophenotype (57.9%). Survival and event-free survival were not influenced by immunophenotype or TCR clonality. The LOD was 1%. Clonal evolution at the relapse period was noted. Conclusions: The overall detection rate of TCR clonality was 74.5%. Survival did not differ by TCR clonality or immunophenotype and age group. Fragment analysis of TCR rearrangement cannot be used to assess MRD due to low sensitivity. Further research on the relationship between prognosis and frequency of TCR rearrangements is needed, using more sensitive methods to detect clonality and monitor MRD.
참고문헌 (23)
- Thörn I, "Minimal residual disease assessment in childhood acute lymphoblastic leukaemia : a Swedish multi-centre study comparing real-time polymerase chain reaction and multicolour flow cytometry", Br J Haematol, 152, pp.743~753 (2011)
- Chiaretti S, "T-cell acute lymphoblastic leukemia", Haematologica, 94, pp.160~162 (2009)
- Brüggemann M, "Acute lymphoblastic leukemia : monitoring minimal residual disease as a therapeutic principle", Semin Oncol, 39, pp.47~57 (2012)
- Vitale A, "Adult T-cell acute lymphoblastic leukemia : biologic profile at presentation and correlation with response to induction treatment in patients enrolled in the GIMEMA LAL 0496 protocol", Blood, 107, pp.473~479 (2006)
- Bene MC, "Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL)", Leukemia, 9, pp.1783~1786 (1995)
- Groenen PJ, "Pitfalls in TCR gene clonality testing : teaching cases", J Hematop, 1, pp.97~109 (2008)
- Thiel E, "Prethymic phenotype and genotype of pre-T(CD7+", ER-)-cell leukemia and its clinical significance within adult acute lymphoblastic leukemia, 1989, pp.73, 1247~1258
- Asnafi V, "Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment", Blood, 101, pp.2693~2703 (2003)
- Brüggemann M, "Has MRD monitoring superseded other prognostic factors in adult ALL", Blood, 120, pp.4470~4481 (2012)
- Brüggemann M, "Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. Procs. Second Int Symp. on MRD Assessment in Kiel, Germany, 18-20 September 2008", Leukemia, 24, pp.521~535 (2010)
- Thörn I, "Applicability of IG", TCR gene rearrangements as targets for minimal residual disease assessment in a population-based cohort of Swedish childhood acute lymphoblastic leukaemia diagnosed 2002-2006, 2010, pp.84, 117~127
- Gameiro P, "Minimal residual disease monitoring in adult T-cell acute lymphoblastic leukemia : a molecular based approach using T-cell receptor G and D gene rearrangements", Haematologica, 87, pp.1126~1134 (2002)
- Chen YL, "BIOMED-2 protocols to detect clonal immunoglobulin and T-cell receptor gene rearrangements in B-and T-cell lymphomas in southern Taiwan", Leuk Lymphoma, 51, pp.650~655 (2010)
- van Grotel M, "Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences", Leukemia, 22, pp.124~131 (2008)
- 김영, "Diagnostic Utility of a Clonality Test for Lymphoproliferative Diseases in Koreans Using the BIOMED-2 PCR Assay", Journal of Pathology and Translational Medicine, 47(5), pp.458~465 (2013), 대한병리학회[DOI]
- Flohr T, "Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia", Leukemia, 22, pp.771~782 (2008)
- Wu D, "High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia", Sci Transl Med, 4, pp.134~ (2012)[DOI]
- van der Velden VH, "Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting", Leukemia, 21, pp.706~713 (2007)
- Kikuchi A, "Clinical significance of TAL1 gene alteration in childhood T-cell acute lymphoblastic leukemia and lymphoma", Leukemia, 7, pp.933~938 (1993)
- Okuda T, "Frequent deletion of p16INK4a", MTS1 and p15INK4b, Blood, pp.1995, 85[DOI]
- Campana D, "Progress of minimal residual disease studies in childhood acute leukemia", Curr Hematol Malig Rep, 5, pp.169~176 (2010)
- de Haas V, "Quantification of minimal residual disease in children with oligoclonal B-precursor acute lymphoblastic leukemia indicates that the clones that grow out during relapse already have the slowest rate of reduction during induction therapy", Leukemia, 15, pp.134~140 (2001)
- Sekiya Y, "Clinical utility of next-generation sequencing-based minimal residual disease in paediatric B-cell acute lymphoblastic leukaemia", Br J Haematol, 176, pp.248~257 (2017)