Translocations and rearrangements in T-cell acute leukemias with the t(11;14) (p13;q11) chromosomal translocations

Chromosomal translocations involving the T-cell receptor alpha and delta genes at q11 on chromosome 14 are the most common cytogenetic abnormalities in patients with T-cell tumors. We have demonstrated that the t(11;14)(p13;q11) translocation in two T-ALL patients involves the J delta region suggesting that the translocation proceeds or coincides with delta gene rearrangement. Additional rearrangements on both normal and translocated chromosomes 14 are described including rearrangement of both Tcr-alpha and Tcr-delta genes, and deletions within the J alpha region. The polyclonality of rearrangements on the normal chromosome 14 in one of the patient samples demonstrates that T-cell receptor rearrangement continues after the translocation event. The identification of clonally expanded rearrangements involving both the Tcr-delta and the Tcr-alpha genes in a single patient suggests a cascade model for delta----alpha expression may be a viable pathway for T-cell maturation.     

A study of chromosome 11p13 translocations involving TCR beta and TCR delta in human T cell leukaemia.

A frequent site of translocation damage in human T-ALL has been localized to a specific region of chromosome band 11p13. Five new T-ALL cases are described which break in the major T-ALLbcr region of 11p13, two involving a novel translocation t(7;11)(q35;p13), with breakage at the T cell receptor (TCR) beta gene from 7q35, and three involving TCR delta from 14q11 in the more common t(11;14)(p13;q11). Analysis of the mechanism of one T-ALLbcr/TCR beta translocation and a previously described t(11;14)(p13;q11) was conducted by genomic cloning of translocation breakpoints, using the polymerase chain reaction (PCR). Both seem to have occurred by recombinase error, but only the t(7;11) showed sequence-specific joining. Nonetheless recombinase mediation of the t(11;14) is implied by the presence of N-region addition (a hallmark of recombinase joins) on both derivative chromosomes. These observations reinforce the view that translocations in the T-ALLbcr region of chromosome 11p13 are a major lesion in human T-ALL. In addition, these can occur by mimicry of VDJ joining, but sequence specificity is not obligatory.     

The T-ALL specific t(11;14)(p13;q11) translocation breakpoint cluster region is located near to the Wilms' tumour predisposition locus

A breakpoint cluster region (T-ALLbcr) has been previously described on 11p13 for T-ALL carrying t(11;14)(p13;q11). One further T-ALL breakpoint is described bringing to 5 out of 6 such translocations which are found to break within a maximum of 6.7 kb on chromosome 11p13. Studies of somatic cell hybrids derived from t(11;14)(p13;q11) T-ALL placed the T-ALLbcr between the genes for catalase (CAT) and the beta-subunit of follicle stimulating hormone (FSHB). This suggested a link between the T-ALLbcr and the Wilms' tumour predisposition locus (WT) since constitutional 11p13 deletions predispose to Wilms' tumour. Utilising somatic cell hybrids from patients with Wilms' tumours and aniridia, we show that while the T-ALLbcr maps distal to the catalase gene at 11p13, it maps outside the shortest region of overlap of a series of 11p13 deletions associated with Wilms'-Aniridia. The data suggest the order of genes at 11p13 to be: centromere-CAT-T-ALLbcr-WT-aniridia-FSHB-telomere. Therefore, the T-ALLbcr must lie very close to but may be distinct from the Wilms' predisposition locus at 11p13.     

Pediatric leukemia/lymphoma with t(8;14)(q24;q11).

A variety of chromosomal translocations occur in pediatric T-cell acute lymphoblastic leukemia (T-ALL) in which a cellular oncogene or growth-related gene is translocated to the alpha/delta locus of the T-cell receptor gene. The t(8;14)(q24;q11) has been described at the cytogenetic and molecular level, but the disease associated with this translocation has not been defined clinically. Fifteen pediatric cases of leukemia/lymphoma with a t(8;14)(q24;q11) chromosomal translocation were collected from previous publications and institutional records. The estimated prevalence of this abnormality among all cases of ALL was 1%. The t(8;14)(q24;q11) disease was characterized by male predominance (10/15), a median age of 5.5 years (range 1.8-17 years), high white blood cell count (median 95 x 10(9)/l), central nervous system infiltration (4/11), bulky extramedullary leukemia (10/11), and T-cell immunophenotype (12/15). The median event-free survival was 4 months, and the median survival, 11 months. Seven cell lines with t(8;14)(q24;q11) were established from six of the cases; four were T-lymphoblastic, one was T-lymphoblastic, but expressed myeloid-related antigens, and two were predominantly myeloid. t(8;14)(q24;q11) leukemia/lymphoma and other ALLs involving 13(q11) have in common a high tumor burden, early spread to extramedullary sites, a propensity to form T-lymphoblastic or T-myeloid cell lines and, usually, an aggressive clinical course.     

Hemophagocytic syndrome complicating T-cell acute lymphoblastic leukemia with a novel t(11;14)(p15;q11) chromosome translocation

A case of hemophagocytic syndrome that developed in a patient with T-cell acute lymphoblastic leukemia (ALL) with a novel chromosome translocation involving 14q11 is reported. A 15-year-old boy with T-cell ALL in relapse showed leukemic cells with an abnormal karyotype of 46,XY,-15,t(11;14)(p15;q11), +der(15)t(15;?)(p11;?). Pancytopenia and extensive hemophagocytosis by macrophages in the bone marrow were observed after reinduction chemotherapy and again at the terminal stage. At autopsy, infiltration of such cells was also found in other organs. The findings suggested occurrence of hemophagocytic syndrome probably associated with cytomegalovirus (CMV) infection. The t(11;14)(p15;q11) may be a novel translocation specific for T-cell ALL, and conceivably, the association of T-cell ALL with the histiocytosis in this patient may not have been coincidental.     

Cloning of the t(11;14)(q13;q32) translocation breakpoints from two human leukemia cell lines

The t(11;14)(q13;q32) translocation has been associated with several subtypes of human leukemia and lymphoma. It has been proposed that this translocation activates a proto-oncogene designated BCL1. In an effort to better understand the mechanism by which this translocation leads to malignancy, we have studied this translocation in two human cell lines. MO1094 and MO2058 were derived from patients with prolymphocytic variants of chronic lymphocytic leukemia. Southern blotting of the MO2058 cell line documented that the translocation linked the Jh region in the immunoglobulin heavy chain gene to the previously described BCL1 major translocation cluster (MTC). Using the polymerase chain reaction, we cloned this translocation and showed that the chromosome 11 breakpoint was within 7 bp of two other samples reported previously. Southern blotting of the MO1094 cell line suggested that the translocation in this cell line might link Jh sequences to a new region in the BCL1 locus on chromosome 11. Therefore, the MO1094 breakpoint was cloned from a genomic library. Comparison with normal cloned DNA from the BCL1 locus showed that the chromosome 11 breakpoint occurred 24 kb telomeric of the MTC. This work reinforces the concept that translocation breakpoints in the BCL1 locus are scattered over at least 63 kb.     

Molecular analysis of breaks in BCL-1 proto-oncogene in B-cell lymphomas with abnormalities of 11q13

The t(11;14)(q13;q32) is a recurring translocation that occurs infrequently but non-randomly in B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's lymphoma, and multiple myeloma. The putative oncogene BCL-1 located at the chromosomal band 11q13 has been cloned previously from a B-cell CLL with t(11;14). We studied the molecular structure of the BCL-1 gene in eight B-cell NHL tumors that exhibited a break at 11q13. The cytogenetic changes in these tumors were t(11;14) in three, t(1;11;14)(q32;q13;q32) in two and dup(11)(pter----q23::11q13----ter) in three. The BCL-1 gene was found to have rearranged in two tumors. By Southern blot analysis of single and double digested DNA from placenta and from the tumors, we mapped the breakpoint in BCL-1 to a 0.5 kb Pst-I-HindIII restriction fragment which was approximately 2kb away from the sites of previously mapped breakpoints. Sequential hybridization of Southern blots of these tumors with different immunoglobulin probes (for J region, Cu, Su) and BCL-1 probe identified co-migrating fragments with Su probe after BamHI restriction digestion. These results demonstrate that translocation breaks in the BCL-1 gene are not clustered in a short stretch of DNA at 11q13, and that the translocation related breaks in the immunoglobulin heavy chain can occur outside the joining region. The implications of these observations to the genesis of chromosomal translocations during B cell development are discussed.     

Translocation t(12;16)(q13;p11) in myxoid liposarcoma of a child and implication of the human int-1 gene in tumorigenesis

Cytogenetic and gene analyses were performed in a child with myxoid liposarcoma (MLS). A reciprocal chromosome translocation t(12;16)(q13;p11) was found in the tumor cells. This result, combined with the previous reports of a similar translocation in adult MLS strongly suggests that this translocation may be a characteristic cytogenetic marker in MLS. The human int-1 gene has been reported to be located close to the 12q13 breakpoint associated with MLS. Therefore, we examined the rearrangement of the human int-1 gene by Southern blotting analysis. When genomic DNAs from the tumor cells were digested with KpnI, EcoRI and BamHI, no difference was seen compared to peripheral blood leukocytes (PBL) DNAs from a normal individual. However, with HindIII digestion there appeared a 3.1 kb fragment in tumor cell DNA as compared to a 2.8 kb fragment in DNAs prepared from normal PBL and the patient's PBL. These findings suggest that the int-1 gene may be implicated in tumorigenesis of MLS with t(12;16)(q13;p11).     

Philadelphia chromosome positive precursor B-cell acute lymphoblastic leukemia with a translocation t(2;14)(p13;q32)

A female patient with precursor B-cell acute lymphoblastic leukemia (precursor B-ALL) was analyzed cytogenetically. Karyotyping of the leukemic cells showed a Philadelphia chromosome (Ph1), and also showed a translocation between 2p13 and 14q32, which is thought to be specific for children with B-cell chronic lymphocytic leukemia. DNA analysis with both conventional and pulsed-field gel electrophoresis revealed the rearrangement of the c-abl gene, the BCR gene outside the 5.8 kb breakpoint cluster region (bcr or M-BCR), and the comigration of an abnormal Not I pHabl 5' and 3'-bcr fragment, indicating the presence of BCR/c-abl recombination. The JH gene was rearranged, but the JK gene showed a germline configuration, as with previously reported cases with a t(2;14). This case is the first report of a patient with Ph1-positive precursor B-ALL, in whom a specific translocation t(2;14)(p13;q32) is found simultaneously.