Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission

Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor-risk entity, commonly associated with FLT3-ITD (internal tandem duplication). Allogeneic stem-cell tranplantation (allo-SCT) is recommended, although studies analysing the outcome of allo-SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo-SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo-SCT was the strongest independent prognostic factor, with a two-year leukaemia-free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0·001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo-SCT in CR1.     

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.     

Low curative potential of bone marrow transplantation for highly aggressive acute myelogenous leukemia with inversion inv (3)(q21q26) or homologous translocation t(3;3) (q21;q26)

Structural rearrangements of the long arm of chromosome 3 involving bands 3q21 and 3q26 and leading either to a paracentric inversion inv (3)(q21q26) or a translocation between both homologous chromosomes – t (3;3)(q21q26) – have been reported in patients with acute myelogenous leukemia (AML), myelodysplastic syndromes, myeloproliferative disorders, and chronic myelogenous leukemia in blast crisis. We describe three patients with de novo AML with these structural abnormalities who received multiple courses of conventional chemotherapy followed by unrelated donor (n=2) and autologous (n=1) bone marrow transplantation (BMT). All three patients had early relapse: patients 1 and 2 had relapse 69 days and 306 days after BMT, respectively, and patient 3 immediately after autologous BMT. Despite further chemotherapy, they died without achieving another remission. These findings, together with other recorded similar cases, show that AML with structural abnormalities of the long arm of chromosome 3 as described has an extremely poor prognosis even with the most potent anti-leukemic treatment modalities. Received: 30 June 1999 / Accepted: 14 December 1999     

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.     

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.     

Secondary acute myeloblastic leukemia with t(16;21)(q24;q22) involving the AML1 gene

A t(16;21)(q24;q22) translocation was detected by fluorescence in situ hybridization in a patient with acute myeloblastic leukemia previously treated for malignant lymphoma. While the breakpoint on chromosome 21 was within the AML1 gene as determined by FISH, the gene partner on chromosome 16 could not be identified. Band 16q24 appears to be rearranged in several types of myeloid proliferation and a review of the literature shows that these rearrangements most often occur in secondary leukemia and myelodysplastic syndrome or are part of complex chromosomal rearrangements.     

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging for acute myeloid leukaemia beyond first remission: a 10-year experience

Between January 1987 and January 1997, 69 eligible patients with acute myeloid leukaemia (AML) in either second (CR2) or third (CR3) complete remission (CR2 = 60, CR3 = 9) underwent 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation (BMT) at the Johns Hopkins Oncology Center. The patients' median age was 27 years (range 1-62) and all received busulphan and cyclophosphamide as their preparative regimen. The probability of event-free survival (EFS) at 5 years was 30% [95% Confidence Interval (CI): 19-42%] for CR2 patients and 22% (3-51%) for those in CR3, with a median follow up of 8 years in the surviving group. The median time to an absolute neutrophil count of 0.5 x 109/l was 45 d (range 20-185). Relapse was the major cause of failure with a relapse rate of 55% in CR2 and 44% in CR3, while the non-relapse, transplant-related mortality rate was 15% in CR2 and 33% in CR3. In univariate analysis, patient age, cytogenetics, white blood cell count at presentation, CR1 duration and the sensitivity of clonogeneic leukaemia (CFU-L) in the graft to 4HC were all prognostic for EFS. Using each of these significant variables in multivariate modelling, patient age and sensitivity of CFU-L to 4HC were determined to be predictors of EFS. 4HC-purged autologous BMT produced results similar to allogeneic BMT for AML patients beyond first remission.     

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.     

Heterogeneity in the breakpoints of chromosome 19 among acute leukemia patients with the t(11;19)(q23;p13) translocation

Gene probes for insulin receptor (INSR) and c-ets-1 were hybridized to metaphase cells from three leukemic patients with the t(11;19)(q23;p13) translocation. Patients 1 and 2 were diagnosed as acute lymphocytic leukemia (ALL) (L2), and patient 3, as acute myelogenous leukemia (AML) (M4). The c-ets-1 gene was demonstrated to have translocated from chromosome 11 to the short arm of the rearranged chromosome 19 (19p+) in all three patients. On the other hand, the INSR gene translocated from chromosome 19 to the rearranged chromosome 11 (11q-) in the AML case, but remained on the rearranged chromosome 19 in the two ALL cases. Thus, the breakpoints of chromosome 19 are different among the patients studied, proximal to the INSR gene locus in the AML case and distal in the two ALL cases. Consequently, the c-ets-1 gene and the INSR gene remain separated in the AML case, whereas they become close to each other in the two ALL cases. Rearrangement of these two genes was studied in the two ALL patients, with no positive data being obtained. The results suggest that there may be heterogeneity in the breakpoints of chromosome 19 among the t(11;19)-associated acute leukemias.     

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.     

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.     

Establishment of a myeloid leukaemia cell line (Kasumi-4) with t(9;22;11)(q34;q11;q13), inv(3)(q21q26) and the EVI1 gene activation from a patient with chronic myelogenous leukaemia in blast crisis

A novel human leukaemia cell line (Kasumi-4) was established from the peripheral blood of a 6-year-old girl suffering from chronic myelogenous leukaemia (CML) in blast crisis. The Kasumi-4 cells had the following characteristic features: undifferentiated blasts which were positive for CD34, CD33 and CD13 surface markers, but negative for myeloperoxidase platelet peroxidase, CD36, CD41 and CD42; chromosome abnormalities of t(9;22;11) (q34;q11;q13), inv(3)(q21q26); and elevated expression of EVI1 gene which is located at chromosome band 3q26. Megakaryocytic maturation was not observed in the liquid culture following the addition of TPA, IL-3, IL-6 or GM-CSF. b2-a2 type of BCR-ABL chimaeric messenger RNA was detected by RT-PCR analysis. This is the first leukaemia cell line with a three-way translocation containing the Ph chromosome and the second cell line with an inv(3)(q21q26). This cell line appears to be useful for studying the mechanisms of leukaemogenesis involving these chromosomal abnormalities and related oncogenes.     

Translocations t(X;14)(q28;q11) and t(Y;14)(q12;q11) in T-cell prolymphocytic leukemia

We report a case of T-cell prolymphocytic leukemia (T-PLL) in a 41-year-old male. Classical cytogenetic, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) studies of a blood sample obtained at diagnosis revealed the co-existence of t(X;14)(q28;q11), t(Y;14)(q12;q11) and a ring chromosome derived from i(8)(q10). Immunophenotypic studies revealed involvement of T-cell lineage, with proliferation of CD4(-) CD8+. The co-existence of two translocations involving both sex chromosomes in a case of T-PLL is rare. Chromosomal instability associated with the disease progression may have allowed the emergence of cell clones with translocations involving the sex chromosomes and the ring chromosome observed.     

Poor survival in t(8;21)(q22;q22)-associated acute myeloid leukaemia with leukocytosis

Abstract: Twenty-nine consecutive cases with a t(8;21)(q22;q22) in the bone marrow (BM) karyotype were retrospectively studied concerning clinical, morphological and cytogenetic data. All had been diagnosed as acute myeloid leukaemia (AML), 27 FAB subtype M2 and two M1, comprising 5% of all cytogenetically analysed AML during 18 yr. Auer rods were the most consistent t(8;21)-associated morphological finding and were demonstrated in 92% of the reviewed BM specimens, whereas BM eosinophilia was seen in only 24%. The median age was 53 yr, and 30% of the patients were >60 yr old. Twenty-four patients had received induction chemotherapy; 22 of these (91%) entered a complete remission (CR). The median survival time in treated patients was 18 months. Leukocytosis at diagnosis (>20×10⁹/l) was significantly (p=0.01) associated with shorter survival time. All four children are still in first CR after 9–80 months. Seven cases (25%) developed granulocytic sarcomas, discovered either at diagnosis (n=4) or at first relapse (n = 3). Secondary chromosome abnormalities were found in 62% of the cases, most often loss of a sex chromosome. The presence of such secondary aberrations did not correlate with any morphological or clinical characteristics, including survival. This first Scandinavian study of AML with t(8;21) corroborates the previous findings that these AMLs are characterized by distinct morphological features, a high frequency of CR and a striking tendency to develop extramedullary leukaemic manifestations. Leukocytosis at diagnosis indicates a less favourable prognosis.     

Severe aplastic anaemia in association with a unique constitutional translocation 46,XY,t(6;10)(q13;q22)c

Severe aplastic anaemia (SAA) is an uncommon disorder which may be associated with several congenital syndromes. However, it has rarely been described in association with a constitutional karyotypic abnormality. The breakpoint of the balanced t(6;10)(q13;q22) translocation described here does not disrupt any currently recognized gene of haemopoietic or stromal importance. This report also highlights the problems inherent in the use of bone marrow transplantation (BMT) for treating multiply transfused aplastic anaemia patients.     

AML bearing the translocation t(11;17)(q23;q21): involvement of MLL and a region close to RARA, with no differentiation response to retinoic acid

We describe a case of acute myeloid leukemia (AML) bearing the translocation t(11;17)(q23;q21). The morphological phenotype represented a monoblastic leukemia, AML French–American–British (FAB) M5a. Further analysis of the translocation revealed an involvement of the mixed-lineage leukemia (MLL) gene and a region closely proximal to the retinoic acid (RA) receptor alpha (RARA) gene. AMLs involving both a rearranged MLL and the 17q21 region, in which the RARA gene is located, have only been described in some individual cases. The functional role of this translocation is still unknown. Rearrangements of the MLL (11q23) gene in AML are usually related to the morphological phenotype FAB M5. In general, they are associated with an adverse prognosis. In acute promyelocytic leukemia, the translocation (15;17)(q22;q11∼21) involving the RARA leads to a maturation arrest that can be overcome by RA, often inducing remission. In other forms of AML, however, the effects of RA are limited and diverse. To study whether RA might have a therapeutical potential in our case, we performed an in vitro analysis of RA effects on AML cells. We found that RA leads to enhanced cell death and up-regulation of CD38 and CD117. However, no hints of RA-induced in vitro differentiation were visible. Our data indicate that in AML cells bearing the t(11;17)(q23;q21), a differentiation arrest that is overcome by RA is not present. On the contrary, RA induces alterations in cellular regulation that are similar to the RA-induced changes observed in early hematogenic progenitors; thus, a possible therapeutical benefit of RA in such cases remains open.     

An atypical myeloproliferative disorder with t(8;13) (p11;q12): a third case

Summary. A 43-year-old male presented with a myeloproliferative disorder with prominent lymphadenopathy. Examination of the bone marrow showed almost complete replacement by a population of cells with an acquired chromosomal translocation t(8;13) (p11;q12). There are two other case reports describing a similar clinical syndrome with t(8;13) (p11;12) as the sole chromosomal aberration in bone marrow cells, suggesting a role for this translocation in the pathogenesis of this myeloproliferative disorder.