T-Cell Receptor α andδGene Assembly in B-Cell Precursor Acute Lymphoblastic Leukemia

1992 ◽  
Vol 7 (5-6) ◽  
pp. 363-370
Author(s):  
Junichi Hara ◽  
Keisei Kawa-Ha
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Cell Precursor

Characterization of immunoglobulin and T-cell receptor gene patterns in B-cell precursor acute lymphoblastic leukemia of childhood.

1990 ◽  
Vol 8 (3) ◽  
pp. 431-442 ◽  
Author(s):  
C A Felix ◽  
D G Poplack ◽  
G H Reaman ◽  
S M Steinberg ◽  
D E Cole ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Leukemic Cells ◽  
Cell Precursor

Immunoglobulin (Ig) and T-cell receptor (TCR) genes were examined in the lymphoblasts of 70 children with immunophenotypically defined B-cell precursor acute lymphoblastic leukemia (ALL). The most frequent genes to rearrange were Ig heavy (H) chain (93%) and TCR delta (79%), followed by TCR gamma (49%), Ig kappa and/or lambda light (L) chain (46%), TCR alpha (46%), and TCR beta (29%). Thus, despite their putative "B-cell precursor" lineage, these leukemias manifest a remarkably high incidence of TCR gene rearrangements. While certain patterns predominate, there is considerable heterogeneity in Ig and TCR genotypes in this disease. No significant associations were found between Ig and TCR genotype and commonly used prognostic factors including age, sex, race, WBC, French-American-British (FAB) subtype, or cytogenetics. However, the lymphoblasts of three of six patients who failed to achieve initial remission had germline patterns of every Ig and TCR gene, a genotype not observed in the leukemic cells from any of the 64 patients who achieved complete remission (p2 = .0007). This study suggests that particular Ig and TCR genotypes may be of clinical relevance in childhood B-cell precursor ALL. The finding of rearranged TCR genes in a large proportion of cases raises fundamental questions about early lineage commitment and lymphocyte differentiation along B-cell and T-cell pathways.

Crosslineage T-Cell Receptor Genes Rearrangements and Active Receptor Editing in B-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4259-4259
Author(s):  
Hanna Makuch-Lasica ◽  
Miroslaw Majewski ◽  
Grazyna Nowak ◽  
Iwona Kania ◽  
Monika Lewandowska ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Light Chain ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Heteroduplex Analysis ◽  
Receptor Editing ◽  
Cell Acute Lymphoblastic Leukemia

Abstract B-cell acute lymphoblastic leukemia (B-ALL) results from clonal expansion of B-lymphocytes derived at different stage of differentiation. Immunoglobulin (Ig) heavy chain genes (IGH), light chain kappa (IGK) and lambda (IGL) genes rearrange during early B-lymphocyte differentiation. T-cell receptor (TCR) genes are considered to rearrange exclusively in normal T lymphocytes, but malignant B lymphoblasts often contain crosslineage rearranged TCR genes. The clonal leukemic cell population, carrying identical copies of rearranged Ig and/or TCR genes, can be identified above 95% of B-ALL patients. In our study Ig/TCR genes rearrangements were detected by multiplex PCR with heteroduplex analysis according to BIOMED-2 protocol. DNA was isolated by column method from mononuclear cells isolated from the peripheral blood/bone marrow samples obtained at initial diagnosis from 36 B-ALL patients. Monoclonal rearrangements of Ig genes were detected in 100% (36/36) of patients. The most frequent rearrangements were observed in IGH genes (94%), including complete IGHV-IGHJ in 83% (30/36) and incomplete IGHD-IGHJ in 22% (8/36) of patients. Among complete IGH rearrangements 2 biallelic rearrangements in IGHV1-7 and IGHJ genes (FR3) were found. Ig light chain genes rearrangements were identified in 26 patients (72%) (including 64% of IGKV-IGKJ, 47% IGKV/intron-Kde, and 22% IGLV-IGLJ) what indicates active receptor editing occurring during B lymphoblasts leukemogenesis. Crosslineage TCR genes rearrangements were found in 97% (35/36) of patients. TCR beta genes rearrangements were detected in 47% (17/36) of patients (complete TRBV-TRBJ in 25% (9/36), TRBD-TRBJ in 6/36 patients - 17%). TRGV-TRGV in 58% (21/36), TRDV-TRDJ in 58% (21/36); 17 monoallelic and 4 biallelic were found. The inactivation of potentially functional IGKV-IGKJ by secondary rearrangements indicates active receptor editing. Our data describe IGK and IGL genes rearrangements incidence, present allelic exclusion and active receptor editing in B-ALL patients. B-ALL lymphoblast undergoes rearrangement on the same IGK allele before IGL genes rearrangement occur. The data may suggest the possible of antigens in B-ALL immunopathogenesis. The results indicate also rearranged IGK, IGL and TCR genes as stable molecular marker for monitoring MRD in B-ALL.

The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2254-2261 ◽  
Author(s):  
Caren Brumpt ◽  
Eric Delabesse ◽  
Kheira Beldjord ◽  
Frederic Davi ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Early Stage ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Cell Precursor ◽  
Increased Risk ◽  
Ontogenic Development

B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) are increasingly treated on risk-adapted protocols based on presenting clinical and biological features. Residual molecular positivity of clonal immunoglobulin (IG) and T-cell receptor (TCR) rearrangements allows detection of patients at an increased risk of relapse. If these rearrangements are to be used for universal follow-up, it is important to determine the extent to which they are informative in different BCP-ALL subsets. We show thatIGH V-D-J rearrangements occur in 89% of 163 BCP-ALL, with no significant variation according to age or genotype (BCR-ABL, TEL-AML1, MLL-AF4, and E2A-PBX1). In contrast,TCRG rearrangements, which occur in 60% of patients overall, are frequent in BCR-ABL and TEL-AML1, are less so in MLL-AF4, and are virtually absent in infants aged predominantly from 1 to 2 years and in E2A-PBX1 ALLs. Incidence of the predominant TCRD Vδ2-Dδ3 rearrangement decreases with age but is independent of genotype. These differences are not due to differential recombination activating gene activity, nor can they be explained adequately by stage of maturation arrest. Analysis of MLL-AF4 BCP-ALL is in keeping with transformation of a precursor at an early stage of ontogenic development, despite the adult onset of the cases analyzed. We postulate that the complete absence of TCRG rearrangement in E2A-PBX1 cases may result from deregulated E2A function. These data also have practical consequences for the use ofTCR clonality for the molecular follow-up of BCP-ALL.

Crosslineage T-Cell Receptor Genes Rearrangements and Active Receptor Editing in B-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4480-4480
Author(s):  
Hanna Makuch-Lasica ◽  
Miroslaw Majewski ◽  
Grazyna Nowak ◽  
Monika Lewandowska ◽  
Iwona Solarska ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Light Chain ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Heteroduplex Analysis ◽  
Receptor Editing ◽  
Cell Acute Lymphoblastic Leukemia

Abstract B-cell acute lymphoblastic leukemia (B-ALL) results from clonal expansion of B-lymphocytes derived at different stage of differentiation. Immunoglobulin (Ig) heavy chain genes (IGH), light chain kappa (IGK) and lambda (IGL) genes rearrange during early B-lymphocyte differentiation. T-cell receptor (TCR) genes are postulated to rearrange exclusively in normal T lymphocytes, but malignant B lymphoblasts often contain crosslineage rearranged TCR genes. The clonal leukemic cell population, carrying identical copies of rearranged Ig and/or TCR genes, can be identified above 95% of B-ALL patients. In our study Ig/TCR genes rearrangements were detected by multiplex PCR with heteroduplex analysis according to BIOMED-2 protocol. DNA was isolated by column method from mononuclear cells isolated from the peripheral blood/bone marrow samples obtained at initial diagnosis from 28 B-ALL patients. Monoclonal rearrangements of Ig genes were detected in 96% (27/28) of patients. The most frequent rearrangements were observed in IGH genes (96%), including complete IGHV-IGHJ in 75% (21/28) and incomplete IGHD-IGHJ in 31% (8/28) of patients. Among complete IGH rearrangements 4 biallelic rearrangements in IGHV1-7 and IGHJ genes (FR3) were found. Ig light chain genes rearrangements were identified in 20 patients (71%) (including 25% of IGKV-IGKJ, 50% of IGKV/intron-Kde, and 25% of IGLV-IGLJ) indicating active receptor editing occurring during B lymphoblasts leukemogenesis. Cross-lineage TCR genes rearrangements were found in 77% (23/28) of patients. TCR beta genes rearrangements were detected in 46% (13/28) of patients (complete TRBV-TRBJ in 32% (9/28), TRBD-TRBJ in 5/28 patients - 18%). TRGV-TRGV were found in 46% (13/28), TRDV-TRDJ in 50% (14/28; 10 monoallelic and 4 biallelic). TCR beta genes rearrangements with presence of TCR gamma genes rearrangements were identified in 25% (7/28) of patients. The identified Ig and TCR rearrangements were stable in patients monitored for minimal residual disease (MRD) and patients with leukemia relapse. The inactivation of potentially functional IGKV-IGKJ by secondary rearrangements indicates active receptor editing. Our data describe IGK and IGL genes rearrangements incidence, present allelic exclusion and active receptor editing in B-ALL patients. B-ALL lymphoblasts undergo many rearrangements on the same IGK allele before they rearrange IGL genes. The data suggest the role of antigen in B-ALL immunopathogenesis. The results indicate also rearranged IGK, IGL and TCR genes as a possible molecular marker for monitoring MRD in B-ALL.

The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2254-2261 ◽  
Author(s):  
Caren Brumpt ◽  
Eric Delabesse ◽  
Kheira Beldjord ◽  
Frederic Davi ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Early Stage ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Cell Precursor ◽  
Increased Risk ◽  
Ontogenic Development

Abstract B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) are increasingly treated on risk-adapted protocols based on presenting clinical and biological features. Residual molecular positivity of clonal immunoglobulin (IG) and T-cell receptor (TCR) rearrangements allows detection of patients at an increased risk of relapse. If these rearrangements are to be used for universal follow-up, it is important to determine the extent to which they are informative in different BCP-ALL subsets. We show thatIGH V-D-J rearrangements occur in 89% of 163 BCP-ALL, with no significant variation according to age or genotype (BCR-ABL, TEL-AML1, MLL-AF4, and E2A-PBX1). In contrast,TCRG rearrangements, which occur in 60% of patients overall, are frequent in BCR-ABL and TEL-AML1, are less so in MLL-AF4, and are virtually absent in infants aged predominantly from 1 to 2 years and in E2A-PBX1 ALLs. Incidence of the predominant TCRD Vδ2-Dδ3 rearrangement decreases with age but is independent of genotype. These differences are not due to differential recombination activating gene activity, nor can they be explained adequately by stage of maturation arrest. Analysis of MLL-AF4 BCP-ALL is in keeping with transformation of a precursor at an early stage of ontogenic development, despite the adult onset of the cases analyzed. We postulate that the complete absence of TCRG rearrangement in E2A-PBX1 cases may result from deregulated E2A function. These data also have practical consequences for the use ofTCR clonality for the molecular follow-up of BCP-ALL.

Clonal Diversity of Ig and T-Cell–Receptor Gene Rearrangements Identifies a Subset of Childhood B-Precursor Acute Lymphoblastic Leukemia With Increased Risk of Relapse

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 952-958 ◽  
Author(s):  
Elaine Green ◽  
Carmel M. McConville ◽  
Judith E. Powell ◽  
Jillian R. Mann ◽  
Philip J. Darbyshire ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Clonal Diversity ◽  
Cell Receptor ◽  
Prognostic Indicators ◽  
Gene Rearrangements ◽  
Risk Patients ◽  
Standard Risk

Abstract Current prognostic indicators such as age, sex, and white blood cell count (WBC) fail to identify all children with more aggressive forms of B-precursor acute lymphoblastic leukemia (ALL), and a proportion of patients without poor prognostic indicators still relapse. Results obtained from an analysis of 65 pediatic B-precursor ALL patients indicated that subclone formation leading to clonal diversity, as detected by Ig and T-cell receptor (TCR) gene rearrangements, may represent a very useful prognostic indicator, independent of age, sex, and WBC. Disease-free survival was significantly shorter in those patients showing clonal diversity at presentation. Furthermore, clonal diversity was detected not only in the majority of high-risk patients who relapsed but was also associated with a high probability of relapse in standard-risk patients. Sixty-five percent (13/20) of standard-risk patients who also showed clonal diversity subsequently relapsed, whereas the percentage of relapses among standard-risk patients without clonal diversity was much lower at 19% (7/36). Continued clonal evolution during disease progression is an important feature of aggressive B-precursor ALL. All 5 patients with clonal diversity who were followed up in our study showed a change in the pattern of clonality between presentation and relapse. This implies an important role for clonal diversity as a mechanism of disease progression through the process of clonal variation and clonal selection. © 1998 by The American Society of Hematology.

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