Analysis of 2 men with t(8;22)(q13;q13) and t(8;14)(q13;q22) chromosomal translocation karyotypes

Male infertility is a multifactorial condition that is closely associated with chromosomal abnormalities. Reciprocal chromosomal translocation (RCT) is a significant structural genetic abnormality. The specific mechanisms of forms of RCT affecting male infertility include the product of chromosomally unbalanced gametes, thereby disrupting the structure and function of important genes responsible for spermatogenesis. RCT breakpoints have been found to disrupt gene structure and function in many medical fields However, the relationship between RCT breakpoints and male infertility remains to be determined. The purpose of this study is to describe 2 male carriers of RCTs 46,XY,t(8;22)(q13;q13) and 46,XY,t(8;14)(q13;q22). Both patients were collected from the second hospital of Jilin University. Semen parameters were detected using the computer-aided semen analysis system. Cytogenetic analysis was performed using standard operating procedure. Related genes on chromosomal breakpoints were searched using Online Mendelian Inheritance in Man. One man had semen parameters within the normal range, but the couple was infertile after 5 years of marriage. The other man showed normal semen parameters, and his wife had experienced 2 spontaneous miscarriages. Using a literature search, the association between chromosome 22q13 breakpoint and fertility were investigated. The results suggest that physicians should focus on the clinical phenotype of the patients and the breakpoints of RCT in genetic counseling. An important gene related to human male infertility is clearly located in chromosome region 22q13, and its function is worthy of further study.     

Multiple myeloma and the translocation t(11;14)(q13;q32): a report on 13 cases

Complex cytogenetic abnormalities have been described in patients with multiple myeloma (MM). To better understand the significance of the most frequent translocation observed in MM, we studied the clinical characteristics of patients with MM and the t(11;14)(q13;q32) abnormality. A search of the cytogenetic database at the Mayo Clinic identified patients with MM and t(11;14)(q13;q32). The medical records were reviewed for the clinical characteristics of these patients. We identified 13 patients with MM and t(11;14)(q13;q32) determined by standard cytogenetic analysis; in 10 patients the abnormality was detected at the time of relapse (three with previously normal results of cytogenetic examination). At the time the translocation was detected, plasma cell (PC) leukaemia was clinically diagnosed in two patients. The median number of circulating PCs, as determined by the cytoplasmic immunofluorescence of T-cell-depleted peripheral blood mononuclear cells, was 1.1 × 10⁹/l (mean 1.74; range 0.0017–6.26 × 10⁹/l). On linear regression analysis there was a strong correlation between the number of circulating PCs and the number of bone marrow PCs. The median survival after demonstration of the translocation was 8.1 months. Of all patients, 10 died of disease progression and three were alive. Patients with MM who have t(11;14)(q13;q32) seem to have an aggressive clinical course, even when the abnormality is detected at the time of diagnosis, with evidence of many circulating PCs.     

Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia

Chromosome anomalies are detected in approximately half of patients with myelofibrosis with myeloid metaplasia (MMM) although none of the most prevalent lesions are specific to the disease. In a prospective cytogenetic study of 81 patients with MMM, we encountered three with an unbalanced translocation between chromosomes 1 and 6 with specific breakpoints; der(6)t(1;6)(q21-23;p21.3). A subsequent Mayo Clinic cytogenetic database search identified 12 patients with this chromosome anomaly among 17 791 consecutive patients. A similar database search from Royal Hallamshire Hospital in Sheffield, UK revealed two additional patients among 8000 cases. The clinical phenotype and survival for each of these 14 patients was typical of MMM. These findings suggested that der(6)t(1;6)(q21-23;p21.3) is a highly specific cytogenetic anomaly that may harbour gene(s) specifically associated with MMM. In a preliminary fluorescence in situ hybridization study, the breakpoints on chromosome 6 in two additional cases were found to be telomeric to the gene for 51 kDa FK506-binding protein (FKBP51).     

Primary cutaneous follicle center lymphoma of the arm with a novel chromosomal translocation t(12;21)(q13;q22): a case report

We report a reciprocal translocation between the long arms of chromosomes 12 and 21, t(12;21)(q13;q22), in a patient with primary cutaneous follicle center lymphoma. Follicle center lymphoma of the skin and follicle center cell lymphoma of the lymph node are morphologically and immunophenotypically very similar. However, the clinical behavior and prognosis of these tumors are different due to the molecular basis of these malignancies. Follicle center cell lymphoma of the lymph node is determined by the presence of a unique translocation between chromosomes 14 and 18, t(14;18)(q32;q21), BCL-2-JH gene rearrangement, that is not present in primary cutaneous follicle center lymphomas. Chromosomal translocations in the primary skin lymphomas have not been previously reported. We hope that our discovery of a new translocation t(12:21)(q13q22) will encourage further investigation into the molecular basis of this translocation and other cytogenetic abnormalities in primary cutaneous B-cell lymphomas.     

Acute megakaryoblastic leukemia with translocation t(1;22)(p13;q13) in a 10-week-old infant.

A 10-week-old girl without Down syndrome developed an acute megakaryoblastic leukemia (AMKL). Bone marrow aspirates and biopsy showed megakaryoblastic infiltration with myelofibrosis. The diagnosis was made based on the findings that the positive reactions of leukemic cells to platelet peroxidase and to monoclonal antibodies which recognize platelet-specific surface glycoprotein (GP) IIb/IIIa and GP78. The blasts also showed myeloid and monocytoid differentiation antigens. The leukemic cells had a karyotype of 46,XX,t(1;22)(p13;q13). Our case and two other infantile cases reported by other investigators establish the novel association of the t(1;22) with AMKL.     

Red cell dimorphism in a young man with a constitutional chromosomal translocation t(11;22)(p15.5;q11.21)

SUMMARY. A constitutional, balanced chromosomal translocation t(11;22)(p15.5;q11.21) was discovered in a tall young man during investigation of a red cell dimorphism. The red cells are predominantly normochromic and normocytic with a small population of hypochromic, microcytic cells. Contained within the regions involved in the translocation are determinants of height (IGF2:11p15.5), red cell haemoglobinization (non-α globin gene complex: 11p15.5) and oncogenesis (cHa-Ras-1, Beckwith-Wiedemann syndrome: 11p15.5; BCR, Burkitts lymphoma, Ewings sarcoma: 22q11.21). To map these regions in the patient, somatic cell hybrids were generated and cell lines that segregated the chromosomes 11, 22 and 22q- were obtained. All 11p15.5 sequences investigated, in particular the whole of the non-α globin gene complex including its 5'and 3'regulatory sequences, were found to be translocated to 22q-. All chromosome 22 sequences studied were missing from the 22q- cell lines, including the proximal anonymous marker D22S24, and therefore assumed to be translocated to 11p+. These results suggest that the non-α globin gene complex has been moved close to the centromeric region of chromosome 22q-. It is postulated that such a positioning subjects the complex to a variegated position-effect bringing about a clonal exclusion of the complex and thus producing a β-thalassaemia trait mosaic.     

Acute basophilic leukaemia and translocation t(X;6)(p11;q23)

We report two infants with acute basophilic leukaemia associated with a t(X;6)(p11;q23) as the sole abnormality. Morphologic evidence of basophilic lineage was provided by light and electron microscopy. Both patients also had a similar presentation on diagnosis, characterized by clinical signs consistent with a hyperhistaminaemia syndrome, i.e. urticarian rashes and gastro-intestinal disorders evocative of peptic ulcer. Immunophenotypes differed in the two patients, one expressing CD24, CD13 and CD33, whereas only CD117 was found in the other.
Basophilic acute leukaemia, a rare group among acute leukaemias, might be nonrandomly associated with a specific chromosomal abnormality, t(X;6)(p11;q23). This new entity might also be identifiable by an uncommon clinical presentation and occurrence in infancy.     

Acute Myelomonocytic Leukemia with Dysplastic Bone Marrow Eosinophils Showing t(5;17)(q13;q11) and a Secondary Chromosomal Aberration, inv(16)(p13q22)

inv(16)(p13q22) is associated with de novo acute myelomonocytic leukemia with dysplastic bone marrow eosinophils (AMML Eo), which has a relatively favorable clinical course with a longer remission duration and better survival prospects. On the other hand, t(5; 17)(q13;q11), although relatively rare, has been reported to be a component of complex chromosomal abnormalities in myelodysplastic syndromes and secondary acute myeloid leukemia (AML). We treated a 29-year-old woman with the first reported case of de novo AMML Eo with inv(16)(p13q22) in addition to t(5; 17)(q13;q11). Although she attained complete remission (CR) immediately after induction therapy, the disease recurred 1 year after the completion of consolidation therapies. She underwent HLA-matched unrelated allogeneic bone marrow transplantation (UBMT), together with a myeloablative conditioning regimen, after achieving a second CR and has survived without a recurrence for more than 24 months since UBMT. In general, certain secondary chromosomal abnormalities are associated with the phenotype of the disease, which retains its essential biologic characteristics established by the primary abnormality. Accordingly, the primary nature of the leukemic cells in this case differs from the findings for core-binding factor AML with inv(16)(p13q22). We believe this report is the first of de novo AMML Eo with t(5; 17)(q13;q11) showing as a secondary chromosomal aberration with inv(16)(p13q22).     

Effect of cytokines on growth and differentiation of leukaemic cells with translocation t(6;9)(p23;q34)

The translocation t(6;9)(p23;q34) is detected infrequently in subtypes of haematological malignancies including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). Although the t(6;9) leukaemia is commonly associated with bone marrow basophilia, the cytological characteristics of leukaemic cells are unclear. In the current study, we examined the in vitro effects of several cytokines on growth and differentiation of t(6;9) leukaemic cells. Isolated bone marrow mononuclear cells from four patients with t(6;9) (two MDS and two AML) were cultured for 14 d in the presence or absence of each cytokine. At the end of culture, viable cells were counted, and their histology was examined. Bone marrow cells obtained from 22 patients (10 AML, six AML from MDS, six MDS) lacking t(6;9) were used as controls. Compared with control cultures, significantly higher numbers of blasts appeared in the culture of bone marrow cells from t(6;9)-positive patients in response to stimulation with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF) or interleukin 3 (IL-3). Stem cell factor (SCF) had little effect. Neutrophil counts were also significantly increased in the presence of G-CSF or IL-3. SCF and IL-3 were potent in increasing basophil counts from t(6;9)-positive cultures. These findings suggest that bone marrow cells obtained from t(6;9) patients are highly sensitive to growth- and/or differentiation-promoting cytokines. Special attention should be paid to the use of "therapeutic" cytokines in these patients.     

Long-term complete haematological and molecular remission after allogeneic bone marrow transplantation in a patient with a stem cell myeloproliferative disorder associated with t(8;13)(p12;q12)

A rare atypical myeloproliferative disorder (aMPD) associated with chromosomal translocations involving the short arm of chromosome 8, region p11-p12 has been described. In most patients, the cytogenetic abnormality is a t(8;13)(p12;q12) that fuses fibroblast growth factor receptor 1, the 8p12 key gene, to FIM/ZNF198 gene. Prognosis is poor with frequent evolution to acute myeloid leukaemia within 1 year of diagnosis. We report a new patient with aMPD with a t(8;13) translocation. Complete haematological, cytogenetic and molecular remission was demonstrated 39 months after allogeneic bone marrow transplantation. This is the first report to demonstrate a molecular remission in this disorder.     

t(9;13)(q34;q12) chromosomal translocation persisting 4 years post autologous bone marrow transplantation for secondary AML despite morphological remission

A 42-year-old male patient with a history of occupational exposure to benzene presented with pancytopenia. His bone marrow showed evidence of trilineage dysplasia and cytogenetic analysis revealed a unique t(9;13)(q34:q12) translocation. Five months after diagnosis he developed secondary AML. He was treated with four courses of chemotherapy and an autologous bone marrow transplantation (BMT). Four years post-transplantation he remains in haematological and morphological remission though the cytogenetic abnormality is still present in all metaphases examined.     

Analysis of T-cell repertoire and mixed chimaerism in a patient with aplastic anaemia after allogeneic bone marrow transplantation

We analysed 26 T-cell receptor (TCR) beta chain subfamilies (VB) of a patient with aplastic anaemia (AA) who underwent allogeneic bone marrow transplantation (allo-BMT). The patient developed pancytopenia at d 80. The patient's T cells were skewed in 10 of 26 TCR-VB on d 83. These TCR-VB, especially VB15, which were almost entirely CD8-positive cells, were skewed throughout her clinical course. Chimaerism analysis of the CD8-positive cells indicated that they were of recipient origin. Therefore, some immune responses induced by the recipient CD8-positive T cells had an important role in pancytopenia in AA patients after allo-BMT.     

Chronic myelomonocytic leukaemia with t(8;9)(p11;q34) in childhood: an example of the 8p11 myeloproliferative disorder?

We describe the case of a 10-year-old girl with chronic myelomonocytic leukaemia with the chromosomal translocation t(8;9)(p11;q34), who had developed tonsillar lymphoma as extramedullary involvement at the initial presentation. The cytogenetic study of the cells in both bone marrow and tonsils demonstrated t(8;9)(p11;q34), despite no malignant features in the bone marrow specimens. She developed acute leukaemic transformation 8 months after diagnosis during chemotherapy for lymphoma. Although etoposide reduced the number of blasts, t(8;9)(p11;q34)-bearing cells were not eradicated. Complete remission was obtained following an unrelated bone marrow transplantation. The clinical characteristics of this patient are similar to those of the patients with t(8;9)(p11;q34 or q32) or t(8;13)(p11;q11 or q12) reported previously. The unusual progression of the disease might be associated with the presence of t(8;9)(p11;q34), suggesting a part in the 8p11 myeloproliferative syndrome.     

A systematic approach to molecular quantitative determination of mixed chimaerism following allogeneic bone marrow transplantation: an analysis of its applicability in a group of patients with severe aplastic anaemia

Mixed chimaerism (MC) following allogeneic bone marrow transplantation (allo-BMT) is defined as the persistent cohabitation of haematopoietic cells from recipients and donors. Its kinetics, clinical implications and more efficient laboratory approaches for MC detection are the object of ongoing research in view of the possibility of developing useful markers. Here we describe a sequential analysis of chimaerism using variable number of tandem repeat (VNTR) polymerase chain reaction (PCR) followed by quantitative, fluorescent labelled, short tandem repeat (STR) PCR. A set of four, highly discriminative VNTR and four STR markers was used to assess chimaerism. Sensitivity and regression analysis indicated that this approach was reliable for routine application in a single BMT centre. We studied 12 patients with severe aplastic anaemia (SAA) who had received allo-BMT, and had been conditioned with cyclosphosphamide (Cy) with or without anti-thymocyte globulin (ATG). We found a 50% prevalence of MC in the whole group, with levels between 4% and 37% of recipient cells. A sustained stable MC pattern after BMT was characteristic of the Cy-only conditioned patients but was also recorded in one patient treated with the Cy + ATG regime who showed a sustained MC pattern over a period of 24 months post-BMT. In none of our patients, MC was associated with an increased risk of graft rejection in a median follow-up of 39.5 months.     

A case of myelodysplasia with eosinophilia having a translocation t(5;12)(q31;q13) restricted to myeloid cells but not involving eosinophils

Summary. A chromosomally abnormal clone characterized by a translocation, t(5;12)(q31;q13), was detected in the marrow of a child with myelodysplasia and associated eosinophilia which included a generalized skin infiltration. Combined immunophenotyping and fluorescence in situ hybridization on interphase bone marrow cells showed that the chromosomal rearrangement was restricted to the granulocyte lineage but was not present in the eosinophils. If the chromosome rearrangement is important in the overproduction of eosinophils in this case, the lineage restriction found suggests that its effect must be indirect.