Single allelic C mu gene rearrangements in patients with T cell and undifferentiated leukemia

By using a panel of monoclonal antibodies in combination with conventional morphological and histochemical studies, seven leukemic patients were diagnosed as having T-cell lymphocytic leukemia (ALL) and three patients were classified as having acute undifferentiated leukemia (AUL). When genomic DNA from each patient was analysed by the Southern blot hybridization technique, two out of seven cases with T-cell ALL and two of three cases with AUL demonstrated immunoglobulin (Ig) mu gene rearrangements. Interestingly, the patterns of C mu gene rearrangement found in these four cases as well as in the T-cell line HSB-2 were quite similar with rearrangement of a single allele and germ line configuration retained in the other allele. Ig gene rearrangement is an essential property of cells of B-lineage, but detection of an Ig gene rearrangement by itself seems insufficient to assign commitment to B-lineage differentiation. The significance of Ig gene rearrangements in T-cell ALL is unclear, but this heterogeneity at the DNA level among T-cell ALL may reflect differences in leukemogeneis and have prognostic and therapeutic implications.     

Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement.

The aim of this study was to identify immunobiological subgroups in 133 infant acute lymphoblastic leukemia (ALL) cases as assessed by their immunophenotype, immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement pattern, and the presence of mixed lineage leukemia (MLL) rearrangements. About 70% of cases showed the pro-B-ALL immunophenotype, whereas the remaining cases were common ALL and pre-B-ALL. MLL translocations were found in 79% of infants, involving MLL-AF4 (41%), MLL-ENL (18%), MLL-AF9 (11%) or another MLL partner gene (10%). Detailed analysis of Ig/TCR rearrangement patterns revealed IGH, IGK and IGL rearrangements in 91, 21 and 13% of infants, respectively. Cross-lineage TCRD, TCRG and TCRB rearrangements were found in 46, 17 and 10% of cases, respectively. As compared to childhood precursor-B-ALL, Ig/TCR rearrangements in infant ALL were less frequent and more oligoclonal. MLL-AF4 and MLL-ENL-positive infants demonstrated immature rearrangements, whereas in MLL-AF9-positive leukemias more mature rearrangements predominated. The immature Ig/TCR pattern in infant ALL correlated with young age at diagnosis, CD10 negativity and predominantly with the presence and the type of MLL translocation. The high frequency of immature and oligoclonal Ig/TCR rearrangements is probably caused by early (prenatal) oncogenic transformation in immature B-lineage progenitor cells with germline Ig/TCR genes combined with a short latency period.     

Unexpected immunoglobulin light chain gene rearrangements in myeloid antigen positive acute lymphoid leukemia.

Blast cells from 10 immunologically diagnosed adult acute lymphoid leukemias expressing myeloid antigens (M+ALL) were studied for immunoglobulin heavy (IgH) and light chain as well as T-cell receptor (TCR)-beta chain gene rearrangements. All but one leukemic isolate met the FAB-criteria for ALL. DNA from 2 patients with pre-pre-B-ALL (CD10-) and 1 patient with common ALL contained rearranged Ig light chain (kappa in two, lambda in one case) in addition to rearranged IgH genes. The TCR-beta chain gene was germline in all pre-pre-B leukemias and rearranged in common ALLs (bigenotypic features). One patient with mature B-ALL showed IgH and light chain gene rearrangements. DNA from 2 pre-T-ALLs contained rearranged TCR-beta chain genes plus rearranged IgH genes in one case. Ig light chain gene rearrangements in immature M+ALL were not associated with gross chromosomal abnormalities except for one Philadelphia chromosome positive case. The occurrence of Ig light chain gene rearrangements in M+ALL with immature lymphoid immunophenotype might represent an hitherto unrecognized aberrant differentiation potential of transformed multipotential stem cells with commitment towards the lymphoid lineage.     

The incidence of T-cell receptor gene rearrangements in childhood B-lineage acute lymphoblastic leukemia is related to immunophenotype and fusion oncogene expression

Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement is conventionally used for assessment of lymphoid malignant cells. TCR genes rearrangements were reported to occur at high frequency in B-lineage acute lymphoblastic leukemia (ALL). Therefore, we have analyzed 83 children with acute B-lineage ALL (67 de novo patients and 19 relapses) by PCR analysis for clonal IgH, incomplete TCRD (Vdelta2-Ddelta3 and Ddelta2-Ddelta3) and TCRG rearrangements. It was shown that clonal cross-lineage TCR rearrangements were associated with more immature immunophenotype (CD34+, CD117+, CyIgM-) of leukemic cells from patients' bone marrow (BM) samples as compared to cell samples without cross-lineage TCR rearrangements. That was equally detected both in de novo and relapsed cases of disease. Low frequency of clonal TCRG rearrangements was associated with expression of E2A/PBX chimeric oncogene. We suggest that TCRG and TCRD clonal rearrangements in leukemic B-cells are associated with early stages of their differentiation.     

Multiparameter analysis of acute mixed lineage leukemia: correlation of a B/myeloid immunophenotype and immunoglobulin and T-cell receptor gene rearrangements with the presence of the Philadelphia chromosome translocation in acute leukemias with myeloid morphology

Morphological, immunological, cytogenetic, and molecular features of 28 cases of acute mixed lineage leukemia (AMLL), defined by the co-expression of lymphoid and myeloid cell surface antigens, were correlated in a multiparameter study. These 28 cases were identified in a series of 260 consecutive acute leukemia cases occurring predominantly in adults and were subdivided into 18 cases of AMLL with myeloid morphology and cytochemistry (AMLL-AML) and 10 cases of AMLL with lymphoid morphology and cytochemistry (AMLL-ALL). A lack of correlation was observed between the expression of B- or T-cell associated antigens with the presence of the expected immunoglobulin (Ig) or T-cell receptor (TCR) gene rearrangements in the AMLL cases with myeloid morphology. Only three of the 18 total AMLL-AML cases, each co-expressing B- and myeloid-associated cell surface antigens (B/My), had Ig heavy chain gene rearrangements with or without rearrangements of TCR genes. Ig light chain genes remained in the germline configuration. Strikingly, these three cases were the only AMLL-AML cases in our series to have the Philadelphia (Ph) chromosome translocation t(9;22)(q34;q11), suggesting that a significant percentage of acute leukemias with myeloid morphology and gene rearrangements may be Ph+ AMLL. The fact that three of the 10 B/My AMLL-AML cases in our series were Ph+ suggests that there may be an increased frequency of Ph chromosome, a translocation associated with a poor prognostic outcome, in B/My AMLL-AML occurring in the adult population. Although most AMLL cases with lymphoid morphology had Ig and TCR gene rearrangements associated with a variety of immunophenotypes and karyotypes, two Ph+ AMLL-ALL cases had many similar features (B/My immunophenotype; IgH with or without TCR rearrangements; Ig light chain genes germline) to their Ph+ AMLL-AML counterparts. However, the Ph+ AMLL-ALL cases differed from the Ph+ AMLL-AML cases by the expression of a more mature B-cell lineage immunophenotype and by their additional cytogenetic changes.     

T cell receptor gene rearrangements in B-precursor acute lymphoblastic leukemia correlate with age and the stage of B cell differentiation

Children with ALL diagnosed at less than 2 years of age have a poor prognosis when compared with older children. In an effort to identify biologic features of ALL in children less than 2 that might explain this difference, we performed extensive immunophenotypic and molecular genetic analyses on a series of patients. For comparison purposes patients were divided into four groups: CALLA- (CD10-) infants less than 2 years of age at diagnosis (n = 10), CALLA- children greater than 2 years of age at diagnosis (n = 10), CALLA+ infants (less than 2 years, n = 21) and CALLA+ children (older than 2 years, n = 21). No immunophenotyping differences in CALLA- or CALLA+ subgroups were identified when cases less than 2 were compared with cases greater than 2 years of age at diagnosis. The most interesting results were in the CALLA- group where 94% of the samples expressed the B cell antigen CD19 but 27% co-expressed CD7. Double labeling experiments confirmed leukemic blast cells co-expressed CD19 and CD7. The double-labeled cells represent either leukemic conversion of a precursor cell which has not yet committed to B or T cell lineage or aberrant expression of these antigens. Molecular genetic studies demonstrated that all samples, regardless of the patients' age or immunophenotype, had rearrangement of the Ig heavy chain gene. The most striking molecular results were in CALLA- patients; in patients less than 2 at diagnosis neither the beta- nor the gamma-chain gene of the T cell receptor (TCR) was rearranged, whereas DNA from 5 of 10 patients over the age of 2 demonstrated beta- or gamma-chain TCR gene rearrangements. The percentage of CALLA+ cases under the age of 2 years with rearrangements in TCR genes is less than that found in CALLA+ cases over the age of 2 years. The finding of no TCR rearrangements in CALLA- ALL and a decreased number of gamma-TCR rearrangements in CALLA+ cases under the age of 2 suggest that age may affect TCR gene rearrangements in lymphoblasts. The molecular differences in TCR gene rearrangements do not appear to correlate with the response to therapy.     

Rearrangement of the T-cell receptor alpha, beta and gamma chain genes in chronic lymphocytic leukemia

Simultaneous expression of mature B-cell and T-cell markers and subsequent abrogation of expression of the T-cell surface markers by cytotoxic chemotherapy was reported earlier in a patient (TG) with chronic lymphocytic leukemia (CLL). In addition to rearrangements of the immunoglobulin (Ig) gene loci correlating with phenotypic data, the T-cell receptor (TCR) alpha, beta and gamma chain genes also displayed clonal rearrangements in peripheral blood lymphocyte DNA of TG. The present case shows that in CLL cells not only the expression of B-cell and T-cell specific differentiation antigens but also the rearrangement of Ig as well as TCR alpha, beta and gamma genes may occur simultaneously.     

Heterogeneity of immunoglobulin gene rearrangements in B-cell lymphomas

We have examined 69 B-cell non-Hodgkin's lymphomas (NHL) for rearrangements of the immunoglobulin (Ig) or T-cell antigen receptor (TCR) genes. The lymphomas were assigned to the categories of the Kiel classification and their B-cell nature was confirmed by immunostaining. Only 2 cases (with CLL) displayed clonal T beta-chain TCR gene rearrangements together with rearranged heavy- and light-chain Ig genes. The remaining 67 lymphomas had a germline beta-chain TCR-gene configuration. Three different patterns of Ig gene rearrangements were identified; (A) presence of both heavy- and light-chain rearrangements (H+L+); (B) rearrangement of heavy-chain gene only (H+L-); (C) heavy- and light-chain genes in germline configuration (H-L-). All the 45 low-grade NHLs and the 4 immunoblastic lymphomas exhibited pattern A and all had their kappa gene rearranged or deleted. Of 24 low-grade lymphomas tested, 13 (54%) had an addition rearrangement of the lambda light-chain gene. In contrast, the 19 high-grade centroblastic (cb) B-NHLs had distinct patterns of Ig-gene rearrangement: 12 with pattern A, 4 with B and 2 with C. In this group only 2 of 17 (12%) cases analyzed had evidence of lambda light-chain rearrangement whereas 12 of 18 (67%) had a kappa gene rearrangement or deletion. In one case expressing sIgM/lambda and with heavy chain Ig-rearrangement, no DNA was available for Ig light-chain analysis.     

Characterization of acute lymphoblastic leukemia of childhood by immunoglobulin and T-cell receptor gene patterns.

Molecular biological studies of immunoglobulin (Ig) and T-cell antigen receptor (TCR) genes provide novel approaches to the identification and characterization of the acute lymphoblastic leukemias (ALL). Such studies greatly enhance our understanding of both the cells of origin in these diseases and the order of assembly of immune receptor genes in B-cells and T-cells. The patterns of Ig and TCR genes in B-cell precursor and T-cell ALL of childhood and ALL of infancy are heterogeneous though generally distinctive. The vast majority of cases of B-cell precursor ALL of childhood rearrange Ig heavy (H) chain genes, and 40-50% rearrange Ig light (L) chain genes. In contrast, in ALL of infancy, Ig genes are frequently germline, indicating generally less mature cells of origin in younger patients. Similarly, the vast majority of cases of T-cell ALL of childhood rearrange TCR delta, gamma, and beta genes and approximately one-half rearrange TCR alpha. TCR gene rearrangements are very common in cases of B-cell precursor ALL, but in patterns different from T-cells. In contrast, T ALL cells only infrequently rearrange Ig genes, and TCR gamma rearrangements are not found in ALL of infancy. The demonstration of lineage non-restricted Ig and TCR gene rearrangements raises questions about lymphocyte development and about the 'precursor' nature of ALL. The identification of generally distinctive patterns of these genes creates a foundation for their utilization as markers of minimal and preclinical disease. The extent to which specific immune receptor gene patterns correlate with clinical outcome in ALL warrants further study.     

A phenotypic and genotypic study of three node-based, low-grade peripheral T-cell lymphomas: angioimmunoblastic lymphoma, T-zone lymphoma, and lymphoepithelioid lymphoma.

Phenotypic and genotypic findings were correlated and compared for 35 specimens taken from 34 patients with three specific types of low-grade peripheral T-cell lymphoma: lymphoepithelioid (LeL), angioimmunoblastic (AILD), and T-zone (TzL) lymphoma. Frozen sections were stained by the double immunoenzymatic method using a combination of the monoclonal antibody Ki-67 for proliferating nuclei and those against lymphocyte surface antigens. Data were correlated by observing clonal rearrangements in the genes of the T-cell receptor beta chain (TCR beta). Of the 35 specimens studied, 32 (91%) were of predominantly CD4+ helper cell proliferation, and 21 (60%) showed the TCR beta gene rearrangement. There were 15 cases of AILD and TzL with predominantly helper cell proliferation, which contained a minimum of 21% CD4+Ki-67+ cells based on the total number of cells present in the specimen. Of these, 13 (87%) showed TCR beta rearrangement. In eight cases, containing a maximum of 20% CD4+Ki-67+ cells, only one (13%) showed any rearrangement. In addition, TCR beta rearrangement was observed in five of the nine cases of LeL, including two cases with only 12% CD4+Ki-67+ cells. For each of the three types, the proportion of CD4+ cells among the Ki-67+ population showed a relatively good correlation with the clonal TCR beta gene rearrangement. Moreover, there was a significant difference (P less than 0.05) in survival curves between groups with and without TCR beta rearrangement, although no obvious plateau was seen. These results suggest that the paucity of tumor cells in these lesions may account for the absence of a detectable band of rearrangements in some patients with one of these three specific types of low-grade peripheral T-cell lymphoma.     

Concomitant rearrangements of T-cell beta- and gamma-chain genes in childhood T-lineage leukemia/lymphoma

Similar to the immunoglobulin (Ig) gene rearrangements in B-lineage cells, identification of T-cell receptor (TCR) gene rearrangements is a novel clonal marker and necessary to establish a T-cell lineage. The function of T-cell gamma-chain (T gamma) gene is still unknown, but because of its shared properties with T-cell alpha-chain (T alpha) and T beta genes, we analysed T gamma gene organization in 10 patients with T-lineage leukemia/lymphoma as well as in non-T lineage leukemias. All 10 cases of T-lineage leukemia/lymphoma, whose phenotypes were different, demonstrated T gamma gene rearrangements as well as T beta gene rearrangements. In contrast, among the non-T-lineage leukemias, the emergence of T beta and/or T gamma gene rearrangements was varied. Based on these findings, concomitant rearrangements of T beta and T gamma genes are characteristic in childhood T-lineage leukemia/lymphoma regardless of their phenotypic differences. Furthermore, no obvious developmental hierarchy was observed between T beta and T gamma gene arrangements in these leukemia/lymphoma cells.     

The pattern of clonal immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements in Chinese adult acute lymphoblastic leukemia patients

We have studied forty Chinese adult ALL patients at newly diagnosis, using standard primers and protocols of BIOMED-2 multiplex PCR, to determine the feasibility of Ig and TCR gene rearrangements as diagnostic and patient-specific MRD-RQ-PCR targets for molecular monitoring. Clonal IGH, IGK, IGL, TCRB, TCRG and TCRD rearrangements were found in 86%, 22%, 9%, 19%, 77%, 55% of adult patients with B-lineage ALL, respectively. While in T-ALL, clonal IGH, TCRB, TCRG and TCRD rearrangements were detected in 6%, 83%, 78%, 33% of patients. Several specialties in the pattern of Ig/TCR gene rearrangements in Chinese adult ALL patients in comparison with those reported for children and adult patients in other countries have been noted. These results are useful for further MRD-RQ-PCR detection and quantification for all patients.     

Validation of BIOMED-2 multiplex PCR tubes for detection of TCRB gene rearrangements in T-cell malignancies.

The BIOMED-2 Concerted Action BMH4-CT98-3936 on 'Polymerase chain reaction (PCR)-based clonality studies for early diagnosis of lymphoproliferative disorders' developed standardized PCR protocols for detection of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements, including TCR beta (TCRB). As no comparable TCRB PCR method pre-existed and only a limited number of samples was tested within the BIOMED-2 study, we initiated this study for further validation of the newly developed TCRB PCR approach by comparing PCR data with previously generated Southern blot (SB) data in a series of 66 immature (ALL) and 36 mature T-cell malignancies. In 91% of cases, concordant PCR and SB results were found. Discrepancies consisted of either failure to detect SB-detected TCRB rearrangements by PCR (6.5%) or detection of an additional non-SB defined rearrangement (2.5%). In 99% of cases (99/100), at least one clonal TCRB rearrangement was detected by PCR in the SB-positive cases. A predominance of complete Vbeta-Jbeta rearrangements was seen in TCRalphabeta(+) T-cell malignancies and CD3-negative T-ALL (100 and 90%, respectively), whereas in TCRgammadelta(+) T-ALL, more incomplete Dbeta-Jbeta TCRB rearrangements were detected (73%). Our results underline the reliability of this new TCRB PCR method and its strategic applicability in clonality diagnostics of lymphoproliferative disorders and MRD studies.     

Rearrangement of T cell receptor beta, gamma, and delta gene loci in human pre-T cell acute lymphoblastic leukemia

Configuration of the T cell receptor (TCR) beta, gamma, and delta chain genes, as well as immunoglobulin (Ig) heavy and light chain genes, was studied in 29 cases of E rosette-negative (pre-T cell) acute lymphoblastic leukemias that lack early B cell (CD19), myeloid (CD33), as well as most T cell associated membrane antigens such as CD1, C4, and CD8, but express CD7, cytoplasmic CD3 (cCD3), and TdT strongly, as well as CD5 and/or CD2 heterogeneously. Hematopoietic progenitor cell markers, namely HLA-DR, J5 (CD10), and My10 (CD34), further characterized this immature T ALL of putative prothymocytic phenotype. Eleven ALLs showed a germline configuration of TCR as well as Ig genes. In three cases, only TCR delta sequences were rearranged, and four additional cases were characterized by recombination of both, TCR gamma as well as TCR delta sequences. Eleven patients showed concurrent rearrangements of TCR beta, gamma, and delta chain genes. An Ig heavy chain rearrangement was observed in one case. These data support the hypothesis that, analogous to pre-B development, a cascade of TCR rearrangements occurs in pre-T cells. Moreover, findings reported here suggest that CD7, as well as CD2 and CD5, antigens appear on precursor cells prior to entry into the thymus and support a model for the developmental hierarchy of TCR genes during early T cell ontogeny.     

Age-related patterns of immunoglobulin and T-cell receptor gene rearrangements in precursor-B-ALL: implications for detection of minimal residual disease.

Detailed Southern blot and PCR analysis of Ig heavy (IGH), Ig kappa (IGK), T-cell receptor delta (TCRD), and TCR gamma (TCRG) genes were performed in 289 children with precursor-B-ALL in order to determine age-related Ig/TCR patterns and their implications for detection of minimal residual disease (MRD). Overall, IGH, IGK, TCRD, and TCRG gene rearrangements were detected in 98, 62, 90, and 58% of patients, respectively. The frequency of IGH and TCRD rearrangements was independent of rearrangements in one of the other three loci, whereas Ig kappa deleting element and TCRG rearrangements preferentially coincided. Southern blot analysis showed that oligoclonality of IGH, IGK, and TCRD was interrelated, that is, oligoclonality in one locus was related with a higher chance of oligoclonality in another locus. Combined Southern blot and PCR analysis revealed that Ig/TCR patterns were age related: children younger than 3 years or older than 10 years showed a higher prevalence of incomplete IGH rearrangements and a lower prevalence of IGK deletions, TCRG rearrangements, and TCRD rearrangements than children between 3 and 10 years. In addition, IGH oligoclonality was more frequent in the younger and older children. These age-related differences probably reflect ALL subsets with different cellular origin and differences in the duration of the preleukemic phase between the initial and final leukemogenetic hit. The more immature Ig/TCR gene rearrangement pattern in children younger than 3 years or older than 10 years resulted in relatively low numbers of potential MRD-PCR targets per patient, particularly if only monoclonal rearrangements were taken into account. These data provide insight into the immunobiological characteristics of Ig/TCR gene rearrangements in childhood precursor-B-ALL and form a useful basis for designing improved strategies for the identification and selection of MRD-PCR targets.     

Phenotypic and genotypic heterogeneity in infant acute leukemia. I. Acute lymphoblastic leukemia

We have studied the immunophenotypic and genotypic features in 35 infants aged less than 1 year with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL). A CD10 (common ALL antigen)-negative, CD19-positive pre-pre-B ALL phenotype was observed in 24 infants. Seventeen of them had blast cells coexpressing myeloid-associated markers such as CD15A (VIM-D5, MZ17) and/or VIM-2, but neither myeloperoxidase nor platelet peroxidase was detected in five of these cases analyzed by electron microscopy. Five patients showed a typical common ALL, five a pre-B ALL phenotype, and one infant was unclassifiable by surface-marker and morphologic analysis. Cytogenetic data, available in 21 of these patients, revealed chromosomal abnormalities involving 11q23 in 10 infants with a CD10-negative pre-pre-B ALL. Immunoglobulin (Ig) and T cell receptor (TCR) gamma, beta and delta gene analysis of 31 infants showed Ig heavy-chain gene rearrangement in all but one patient with evidence for clonal evolution in six and kappa-light-chain rearrangement in three infants. TCR beta-chain and TCR gamma-chain rearrangement occurred in six and five patients respectively, while TCR delta-chain rearrangement was identified in 15 patients. Our data indicate that ALL in infancy may present with heterogeneous immunophenotypic and genotypic features. The high frequency of coexpression of B-lineage and myeloid surface markers as well as of chromosomal rearrangement involving 11q23 suggests that the clonogenic cell of infant ALL may relate to a multipotent progenitor cell in most cases.     

Stability of multiple antigen receptor gene rearrangements and immunophenotype in Hodgkin's disease-derived cell line L428 and variant subline L428KSA

The Hodgkin's disease (HD) derived cell line L428 and a phorbol ester-selected subline L428KSA, which have been independently passaged in tissue culture for several years, were studied for possible antigen receptor gene and immunophenotypic differences. Multiple but identical alterations of these genes were found, including: the deletion of one and rearrangement of the other immunoglobulin (Ig) heavy chain allele; the rearrangement of one kappa and one lambda light chain allele; and the rearrangement of one T cell receptor (TCR) beta allele. Restriction mapping of the Ig heavy chain locus indicated that rearrangement of the retained allele produced a JH-C gamma 4 fusion product by an isotype switch mechanism. The 14q+ chromosome [t(14q32;?)] present in both cell cultures derived either from translocation 5' (telomeric) to the rearranged JH allele or 3' (centromeric) to the deleted Ig heavy chain allele and did not involve detectable rearrangement of the c-myc, bcl 1, or bcl 2 oncogenes. No differences in the immunophenotype were found between the L428 and L428KSA cells: both expressed leukocyte activation antigens and some determinants associated with myelomonocytic cells but no lymphoid markers. It is postulated that these phenotypic characteristics derived from secondary genetic events/differentiative reprogramming which produced extinction of primary lymphoid characters, including terminal deoxynucleotidyl transferase (TdT) essential to generation of the Ig and TCR gene rearrangements, and expression of an incomplete set of myelomonocytic markers.     

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

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.