Pre-B-cell leukemia with a t(8; 14) and a t(14; 18) translocation is preceded by follicular lymphoma

We have performed gene rearrangement studies on the leukemic blasts of a patient with acute pre-B-cell leukemia. The patient had a 5 year history of follicular lymphoma, which developed into acute pre-B-cell leukemia. The leukemic blasts revealed a karyotype with two translocations, t(8; 14) and t(14; 18), characteristic for Burkitt's lymphoma and follicular lymphoma. The cells are TdT positive, do not possess surface immunoglobulin, and they show immunoglobulin gene rearrangement. The mu heavy chain and kappa light chain constant (C mu and C kappa) loci are deleted, while the gamma and lambda light chain constant (C gamma and C lambda) region genes are rearranged. Both alleles of the heavy chain joining segment (JH) are rearranged on chromosome 14q+, one of them with the bcl-2 oncogene from chromosome 18. The breakpoint of the t(14; 18) translocation occurs in the major breakpoint cluster region in the 3' untranslated region of bcl-2. On chromosome 8 a c-myc rearrangement was mapped immediately 5' to the c-myc first exon in a region involved in sporadic Burkitt lymphoma. The data are consistent with our previous hypothesis on the evolution of B-cell malignancies: a rare pre-B cell develops a t(14; 18) translocation during immunoglobulin VDJ joining that results in an expansion of a follicular lymphoma clone carrying an activated bcl-2 gene. Within the clone of pre-B cells a second translocation, t(8; 14), occurs during heavy chain isotype switching that results in the deregulation of the c-myc involved in the translocation.     

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.     

Rearrangements on chromosome 11q23 in hematopoietic tumor-associated t(11;14) and t(11;19) translocations.

We previously demonstrated that the breakpoint of t(11;14)(q23;q32) in the RC-K8 B cell lymphoma cell line lies between CD3 and THY1/ETS1 on chromosome 11q23, and we cloned this region and named it the rck locus. Pulsed-field gel electrophoresis showed that the rck probe B (distal to the breakpoint) and the porphobilinogen deaminase (PBGD) probe detect the same germ line band and also the same rearranged band when DNA from RC-K8 cells was digested with NotI enzyme. Furthermore, Southern blot analysis with somatic cell hybrids showed that the PBGD gene moved to the 14q+chromosome, which confirmed PBGD to be more distal to the centromere than the rck locus. These data allowed us to construct the following order of genes: 11 cen-q23-CD3-rck-PBGD-THY1/ETS1. In this study, three infantile leukemia cell lines with t(11;19)(q23;p13) translocation were also analyzed by pulsed-field gel electrophoresis. CD3D probe detected the rearranged bands in DNA from two of them after digestion with NotI and SacII enzymes, demonstrating that the breakpoints of both cell lines were estimated to be within 360 kilobases of CD3D.     

Molecular cloning of the chromosomal breakpoint of a B-cell lymphoma with the t(11;14)(q23;q32) translocation

The breakpoint of t(11;14)(q23;q32) chromosome translocation in a B-cell lymphoma line, RC-K8, was cloned. Immunoglobulin heavy chain (IGH) constant gene, C gamma 2 at the 5' end, was involved in this translocation, and the DNA segment juxtaposed to the C gamma 2 was proved to be derived from chromosome 11 by somatic cell hybrid study. The normal counterpart of chromosome 11 was also isolated. With a DNA probe near the breakpoint of chromosome 11, Southern blot analysis of RC-K8 and 10 other cases with translocation involving the 11q23 region was conducted, but no rearrangement bands have been observed thus far except for RC-K8.     

Detection of minimal residual disease in leukemic patients with the t(10;14)(q24;q11) chromosomal translocation

Early relapse and minimal residual disease during clinical remission was examined in two patients having acute T-cell leukemia/lymphoma with the t(10;14)(q24;q11) chromosomal translocation. Molecular probes which can detect T-cell receptor alpha/delta clonal rearrangements and a TCL-3 probe which can detect the clonal rearrangement due to the chromosomal translocation failed to detect the leukemic clones during clinical remission by Southern filter hybridization. However, application of the polymerase chain reaction technology in amplification of the t(10;14)(q24;q11) chromosomal juncture during clinical remission permitted us to increase the detection level of neoplastic cells up to 1 leukemic cell/125,000 normal cells using 1 microgram of DNA. Amplified junction fragments were detected in both patients. In one case, during the period of clinical remission no amplified fragments were detected.     

Molecular analysis of a t(9;14)(p11;q32) translocation occurring in a case of human alpha heavy chain disease

We performed the cloning and sequencing of the der(14) breakpoint of a new chromosomal translocation involving the 14q32 immunoglobulin locus. This t(9;14)(p11;q32) translocation was found in a case of malignant lymphoma occurring in human alpha heavy chain disease. A rearranged alpha 1 gene fragment was cloned and shown to contain chromosome 9 information by Southern blotting on sorted chromosomes and by in situ hybridization. Sequence analysis of the junction point region established that the breakage occurred 3' to the heavy chain joining region. In contrast to the data obtained in other translocations affecting 14q32 immunoglobulin locus, the recombination did not involve the immunoglobulin heavy chain locus specific recombination signals on chromosome 14, or homologous sequences on chromosome 9. In the present case, the existence of two almost perfect inverted repeats flanking the junction point suggests that the translocation originated from a local pairing of the two chromosomes 9 and 14. Chromosome 9 fragments sequenced in the vicinity of the breakpoint did not share significant homology with sequences listed in GenBank and EMBL data bases.     

Molecular characterization of a t(11;14)(q23;q32) chromosome translocation in a B-cell lymphoma

We have analyzed the molecular features of a t(11;14)(q23;q32) chromosome translocation of a cell line established from a B-cell lymphoma. Somatic hybrid cells carrying the 11q- and/or 14q+ chromosome(s) were produced in order to map the breakpoints. Southern blot analyses of DNAs from these hybrid cell lines together with various probes from the IGH locus on chromosome 14 and the ETS-1 and CD3 genes on chromosome 11 showed that the breakpoints of the translocation occurred between the constant regions of the C phi gamma and C gamma 2 genes on chromosome 14 and between the CD3 and ETS-1 genes on chromosome 11. The t(11;14)(q23;q32) translocation does not seem to involve the same mechanism that is responsible for translocations occurring at the immunoglobulin heavy chain joining segment (JH).     

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.     

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.     

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.     

TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11)

We have cloned 70 kb of DNA from chromosome 11p13 at the site of a recurrent translocation in T-cell leukaemia (T-ALL): t(11;14)(p13;q11). The translocation involves the TCR-delta gene on 14q11 and a new site on 11p13. Two new and 10 previously identified translocations all mapped within 25 kb on 11p13, the 11p13 T-cell translocation cluster (11p13 ttc). A search for expressed sequences surrounding the breakpoint cluster region on 11p13 identified a gene telomeric of all breakpoints which is overexpressed in three T-ALL samples with a t(11;14). The gene T-cell translocation gene (TTG-2) encodes a small cysteine-rich protein. Forty-eight per cent of the amino acids are identical with another translocation-deregulated gene, TTG-1 (T-cell translocation gene 1 or rhombotin) in 11p15. There are two copies of a cysteine-rich motif in both proteins. Two tandem copies of the same cysteine-rich motif are also present in the recently described lin-11, isl-1 and mec-3 gene products, and one motif is found in the CRIP protein. Therefore the proteins encoded by these two translocation-deregulated genes belong to this new class of cysteine-rich proteins with the 'LIM' motif, which are important in normal development.     

A novel translocation t(3;22)(q21;q11) involving 3q21 in myelodysplastic syndrome-derived overt leukemia with thrombocytosis

We report here a novel translocation t(3;22)(q21;q11) in myelodysplastic syndrome (MDS)-derived overt leukemia with thrombocytosis. A 44-year-old female was initially diagnosed as MDS with a low platelet count and normal karyotype. After 4 months, blood leukemic cells and platelets rapidly increased concomitantly and a diagnosis of acute myeloblastic leukemia (AML M1) was made. Chromosome analysis showed 46, XX, t(3;22)(q21;q11) in 14 of 20 metaphases. Fluorescence in situ hybridization analysis confirmed both the der(3)t(3;22) and the der(22)t(3;22). Our results suggest that unidentified gene(s) at 3q21 breakpoint may be implicated in the pathogenesis of abnormal thrombopoiesis as observed in the 3q21q26 syndrome.     

Disruption of the RanBP17/Hox11L2 region by recombination with the TCRdelta locus in acute lymphoblastic leukemias with t(5;14)(q34;q11).

The t(5;14)(q33-34;q11) translocation constitutes a recurrent rearrangement in acute lymphoblastic leukemia involving the T cell receptor (TCR) delta locus on chromosome 14. Breakpoint sequences of the derivative chromosome 5 were isolated by application of a ligation-mediated PCR technique using TCR delta-specific primers to amplify genomic DNA from the leukemic cells of a patient with t(5;14). Through exon trap analysis, we identified various putative exons of the chromosome 5 target gene of the translocation; compilation of sequence information of trapped exons and available expressed sequence tags (ESTs) from the GenBank database allowed us to assemble 1.2 kb of the cDNA. Full-length cDNAs were isolated from a human testis cDNA library and sequence analysis predicted a putative Ran binding protein, a novel member of the importin-beta superfamily of nuclear transport receptors, called RanBP17. The t(5;14) breakpoint maps to the 3' coding region of the gene. The breakpoint of a second t(5;14) positive patient was mapped about 8 kb downstream of the most 3' RanBP17 exon and 2 kb upstream of the first exon of the orphan homeobox gene, Hox11L2. In both cases TCR delta enhancer sequences are juxtaposed downstream of the truncated or intact RanBP17 gene, respectively on the derivative chromosome.     

T-cell acute lymphoblastic leukemia with t(11;14) in children.

We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(11;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(11;14), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t(11;14)(p13;q11) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance.     

T-Cell Acute Lymphoblastic Leukemia with t(11;14) in Children

We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(11;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(11;14), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t(11;14)(p13;q11) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance.     

VP16 hypersensitivity and increased faulty recombination in ataxia telangiectasia lymphocytes characterizedby the tandem translocation t(14; 14)(q11;q32)

Ataxia telangiectasia (AT) patients show variable degrees ofimmunodeficiency and a higher than normal predisposition tolymphoid malignancies. At cells are characterized by spontaneouschromosome instability resulting in chromosome breakageand innon random chromosome rearrangements. Sequential cytogeneticstudies on T-lymphocytes from an AT patient showed theprogressivedevelopment of a clone bearing a tandem translocation t(14;14)(q11;q32). The abnormal clone had spontaneous chromosomerearrangements. Compared to non clonal cells, the abnormal clonedisplayed a higher frequency of spontaneous chromosome rearrangements.In only the clonal cells we observed two particular and predominantrearrangements: isodicentric chromosomes and telomeric associationswhich may derive from faulty recombination. Chromosome instabilityinduced by the etoposide VP16, a DNA topoisomerase II inhibitor,was evaluated in terms of chromosome breakage and SCE frequency.T-lymphocytes from the AT patient showed hypersensitivity toVP16 significantly higher than normal T-lymphocytes. The chromosomeinstability induced by VP16 is significantly higher in clonalthan in non clonal cells, whilst the chromosome instabilityinduced by the radiomimetic drug bleomycin is not significantlydifferent in the two AT lymphocyte subpopulations. The differentspontaneous chromosome instability in clonal and non clonalcells together with their different behavior after treatmentwith only VP16, suggest that clonal cells bearing the tandemtranslocation could have increased faulty recombination. Giventhe presence of translocations t(14; 14)(q11;q32) in T-prolymphocyticleukemias and T-cell tumors of non AT patients, our findingssuggest that VP16 could be considered an antineoplastic treatmentparticularly indicated in these patients.     

Variant t(2;11)(p11;q13) associated with the IgK-CCND1 rearrangement is a recurrent translocation in leukemic small-cell B-non-Hodgkin lymphoma.

Classical t(11;14)(q13;q32) involving IGH-CCND1 is typically associated with aggressive CD5-positive mantle cell lymphoma (MCL). Recently, we identified the IGK variant of this translocation, t(2;11)(p11;q13), in three patients with a leukemic small-cell B-non-Hodgkin lymphoma. In all cases, rearrangements of the IGK and CCND1 genes were demonstrated by fluorescence in situ hybridization. Moreover, we mapped the 11q13 breakpoint of this variant translocation in the 3' region of CCND1 which contrasts with the 5' breakpoints in a standard t(11;14)(q13;q32). Expression of cyclin D1 was shown in two cases analyzed either at diagnosis or during disease progression. All three patients were asymptomatic at presentation and no initial therapy was required. One patient died of a progressive disease 58 months from diagnosis, and two patients showed stable disease after 12 months of follow-up. In two analyzed cases, mutated IGVH genes were identified. Our findings indicate that variant t(2;11)(p11;q13) does not typify a classical MCL but possibly a more indolent leukemic lymphoma originating from an antigen experienced (mutated) B cell.