A cDNA clone representing the gene encoding the fi chain of the human T-cell antigen receptor has been isolated recently. By using fragments of this cDNA as hybridization probes in Southern blot analysis of restriction endonuclease-digested genomic DNA, we have now examined the structure of the gene in DNA from 26 patients with acute leukemia and from 23 normal individuals. We have found that the T-cell antigen receptor gene has undergone somatic rearrangement in 14 of 14 patients with the phenotypic diagnosis of T-cell acute lymphoblastic leukemia. In this group of patients, similar patterns of rearrangement appear to occur in different patients. This finding suggests that there is either a limited repertoire of possible rearrangements or an association between the development of leukemia and specific patterns of rearrangement. DNA from 6 patients with acute myeloblastic leukemia, 6 patients with non-B, non-T acute lymphoblastic leukemia, and 23 nonleukemic individuals showed no rearrangement or polymorphism. One case of T-cell acute lymphoblastic leukemia, however, showed rearrangement of both the T-cell receptor f3 chain and the constant region of the immunoglobulin gene. Studies with mixtures of DNAs from leukemic bone marrow cells and cultured skin fibroblasts, as well as with remission and relapse marrow DNAs from the same patients, indicate that this technique can detect 1% leukemic cells in a mixed population. In addition, DNA from the marrow of a patient in relapse contains a similar rearrangement to that found in the marrow sample taken at the time of diagnosis, which suggests that the original clone of leukemic cells was responsible for relapse. Our results indicate that assessment of rearrangement of the T-cell antigen receptor gene will be valuable in the diagnosis and management of leukemia and can be used to evaluate clonality in T-cell neoplasia.The recent isolation of cDNA clones for the mouse and human T-cell antigen receptor has made possible a number of studies regarding the ontogeny of T cells (1-3). The general genomic structure of the T-cell antigen receptor gene is similar to that of the immunoglobulin genes in that there are variable (V) regions, diversity (D), joining (J) regions, and constant (C) region elements (4, 5). Similar to immunoglobulin, the T-cell antigen receptor must be able to recognize a vast array of foreign antigens. This similarity between the immunoglobulins and the T-cell antigen receptor with regard to gene structure and protein function suggests that a similar mechanism for generating diversity of the receptor molecule is functional in both B cells and T cells.In the case of B cells, diversity is achieved in part by somatic rearrangement of the immunoglobulin genes prior to the production of a functional immunoglobulin molecule. Such rearrangements are detected by Southern blot analysis of DNA isolated from B cells. Similar rearrangements have been found in mouse and human T-cell lines when the T-cell antigen receptor gene has been used as a probe (2, 6). I...

Abstract. A 6-yr-old girl with T cell acute lymphoblastic leukemia (ALL) is described. She had a mediastinal mass and her leukemic cells expressed T cellassociated antigens (Leu 1+, OKT3+, OKT9+, and OKTIO+). When we examined genomic DNA from the leukemic cells, we detected Ig M-chain gene rearrangement with germ-line configuration of light chain genes. As reported recently, detecting Ig gene rearrangement has become an important procedure for further classifying B cell precursor cells. This case, however, suggests that there is also heterogeneity among patients with T cell ALL, not only at the level of cell surface phenotypes, but also at the level of the Ig gene. These findings have major implications when we consider both the ontogenesis of these leukemic cells and the normal differentiation of human lymphocytes.

In addition to conventional morphological, histochemical and immunological marker studies, cells from 60 children with leukaemia were further analysed using the Southern blot hybridization technique to look at differences in the organization of immunoglobulin (Ig) genes. Of the 60 patients studied by conventional means, 47 were diagnosed as acute lymphocytic leukaemia (ALL) and 13 as non-lymphocytic leukaemia. Seven patients were initially classified as T ALL and 40 as non-T, non-B ALL. Further subclassification of the 40 patients with non-T, non-B ALL indicated three pre-B ALL and 29 patients diagnosed as common ALL, expressing Ia and CALLA antigens. All 29 patients with common ALL demonstrated C mu gene rearrangements with or without light chain (kappa and lambda) genes rearrangement. Based on the developmental hierarchy of Ig gene rearrangement, it was possible to further subclassify the patients with common ALL into different stages of B cell development. Eight (of the 40) patients with non-T, non-B ALL were identified as CALLA- but further analysis indicated T-lineage origin in two patients and three patients were reclassified as acute undifferentiated leukaemia (AUL). C mu gene rearrangements were detected in two patients with T ALL, two patients with AUL and one patient with acute myelogenous leukaemia (AML). In contrast to the patients with common ALL, Ig gene rearrangement observed in these non-B-lineage cells was restricted to a single C mu gene while retaining germ-line configuration of the other allele of the C mu gene and both light chain genes.