Hematologic malignancies with t(4;11)(q21;q23)--a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. European 11q23 Workshop participants

A total of 183 hematologic malignancies with t(4;11)(q21;q23), including five variant translocations, were collected by the Workshop. Clinical, morphologic and immunophenotypic features were compiled, and karyotypes with variant t(4;11) or secondary chromosomal aberrations were reviewed. All cases were acute leukemias (AL): 173 acute lymphoblastic leukemias (ALL), six acute myeloid leukemias (AML), three unclassifiable AL, and one biphenotypic AL. Ten patients had treatment-associated AL. Females were overrepresented (104 vs 79) and the age distribution was clearly nonrandom; 34% of the cases occurred in infants below the age of 12 months. The remaining AL were evenly distributed among the other age groups, with the oldest patient being 79 years old. An increased white blood cell count (WBC) was reported in more than 90% of the cases, with hyperleukocytosis (> or =100 x 10(9)/l) in 64%. Additional chromosomal changes were detected in 55 (30%) cases, most often gain of the X chromosome, i(7)(q10), and trisomy 8, with frequent breakpoints in 1p36, 1q21, 7q10, 11p15, 12p13, 17p11, and 17p10. All recurrent secondary changes resulted in genomic imbalances, in particular gains of 1q, 7q, 8, and X and losses of 7p and 17p. Event-free and overall survival (EFS and OS) could be ascertained in 170 and 171 patients, respectively. Kaplan-Meier estimates of EFS and OS showed no differences with regard to gender, WBC, or presence of secondary chromosomal abnormalities, and there was no increase of EFS or OS among the 55 cases that had undergone bone marrow transplantation. However, age had an important prognostic impact, with significantly (P < 0.0001) longer EFS and OS in children 2-9 years old than among infants and younger children, patients aged between 10 and 39 years and older adults.     

Hematological malignancies with a deletion of 11q23: cytogenetic and clinical aspects. European 11q23 Workshop participants

OBJECTIVE: Using receiver-operating characteristic (ROC) curves, we tried to determine the diagnostic threshold of amniotic fluid index (AFI) that will identify abnormal fetal size (birth weights under 2500 g or at least 4000 g) at 37 weeks or beyond. METHODS: We analyzed prospectively over 2 years all parturients with intact membranes and known AFI in early labor. Patients with the following conditions were excluded: pregestational or gestational diabetes, known anomalies, and preterm labor. Two ROC curves were constructed, and the areas (+/- standard error of the mean [SE]) under the curves were calculated. P < .05 was considered significant. RESULTS: Of the 1038 subjects meeting study criteria, 3.6% and 11.5% gave birth to infants who were small for gestational age (SGA) or macrosomic, respectively. Overall, 28.7% had oligohydramnios (AFI at most 5.0 cm) and 3.6% had hydramnios (AFI at least 24.0 cm). Small for gestational age was more common in patients with AFI at most 5.0 cm (6.4%) than in those with adequate fluid (AFI 5.1-23.9; 2.5%), or hydramnios (2.7%; P = .012). Macrosomic newborns were less likely to be born to women with oligohydramnios (7.7%) than to those with adequate amniotic fluid (13.1%) or hydramnios (13.5%). Areas under ROC curves are not significantly different from the area under the nondiagnostic line, indicating that AFI (0-34 cm) cannot differentiate between newborns under 2500 g and at or over 2500 g or under 4000 and at or more 4000 g. CONCLUSION: Intraparterium AFI appears to be a poor screening test to identify risk for delivery of SGA or macrosomic fetus.     

The t(10;11)(p12;q23) translocation in acute leukaemia: a cytogenetic and clinical study of 20 patients. European 11q23 Workshop participants

The clinical, haematological and cytogenetic data for 20 patients with an acquired abnormality of 11q23 and 10p have been reviewed at this workshop. Patients predominantly presented with de novo AML M5a and the most common cytogenetic finding was an inversion of part of the long arm of chromosome 11 followed by a translocation between 11q and 10p. Band p12 represented the most common breakpoint on chromosome 10. The t(10;11) subgroup defined a subset of younger 11q23 patients, the majority of whom achieve a first complete remission despite the differing treatment regimens.     

High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies

Abnormalities involving the 14q32 region are recurrent chromosomal changes in plasma cell malignancies. Recent preliminary molecular analyses found IGH rearrangements in almost 100% of human myeloma cell lines and in 75% of patients. However, no systematic study analyzing the nature of the partner chromosomal regions have been reported thus far. To define the exact incidence of illegitimate IGH rearrangements and the respective incidence of partner genes cloned to date, we analyzed 141 patients with either multiple myeloma (MM, n = 127) or primary plasma cell leukemia (PCL, n = 14) using fluorescence in situ hybridization. The overall incidence of illegitimate recombinations was 57% (80 of 141 patients). Analysis of this incidence according to Durie and Salmon stage, patients' status, i.e., MM versus primary PCL and diagnosis versus relapse, immunoglobulin type and subtype, and beta2-microglobulin value, did not show any correlation. To analyze the nature of the partner chromosomal region, we selected probes specific for the following genes: FGFR3 (4p16), MYC (8q24), CCND1 (11q13), MAF (16q23), and BCL2 (18q21). These probes, combined with differentially labeled 14q32 probes, were used for dual-color fluorescence in situ hybridization on interphase plasma cells. Among the 80 patients with illegitimate IGH rearrangement, we identified 23 IGH-CCND1 fusion cases [i.e., t(11;14)], 17 IGH-FGFR3 fusion cases [i.e., t(4;14)], 3 IGH-MYC fusion cases [i.e., t(8;14)], and only one IGH-MAF fusion case. No IGH-BCL2 fusion case was detected. In 37 of 80 patients, none of these partner genes was involved. Analysis of cases with specific translocations according to their bioclinical features at diagnosis did not show any correlation. This study demonstrated that CCND1 and FGFR3 genes are involved together in about 50% of MM and primary PCL patients with illegitimate IGH rearrangements.     

A der(22)t(9;22)(p13;q11) in bone marrow cells of a patient with multiple myeloma: a variant of the t(9;14)(p13;q32) associated with a subset of lymphoplasmacytoid lymphoma

An adult cattle egret (Bubulcus ibis) caught in Kobe of Hyogo Prefecture, Japan, in December 1995 died of a severe infection associated with the trematode parasite Pegosomum sp. At necropsy, 22 trematode parasites were found in the lumen of the bile duct, and the duct wall was markedly thickened. Histopathologically, severe cholangitis and cholecystitis were observed in close association with the parasites in the bile duct. Severe Pegosomum sp. infection may be one of the factors contributing to the mortality of wild cattle egrets. This is the first reported case of the genus Pegosomum infection in wild birds of Japan.     

Pediatric primary diffuse large cell lymphoma of bone with t(3;22)(q27;q11)

PURPOSE: A child with a primary lymphoma of bone (PLB) with a t(3;22)(q27;q11) is described. METHODS: An 11-year-old boy had a 5-week history of back pain and a destructive lesion of S1 that contained an epidural component. Histologic evaluation of a biopsy confirmed the diagnosis of diffuse large B-cell non-Hodgkin lymphoma. Karyotypic analysis disclosed a t(3;22)(q27;q11), but the amount of tumor tissue was insufficient for molecular studies of the BCL-6 gene. RESULTS: The patient remains free of disease 4 years after completion of intensive systemic chemotherapy and intrathecal chemotherapy. CONCLUSIONS: The lymphoma in the patient described in this report is highly unusual because of the coexistence of pediatric PLB and a t(3;22)(q27q11).     

Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22): an additional deletion in 9q is an adverse prognostic factor

The translocation t(8;21)(q22;q22) occurs in 6 to 12 percent of patients with AML, and usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. The influence of additional chromosome aberrations on the clinical outcome of patients with t(8;21) is unclear. We analyzed 51 cases of acute myeloid leukemia carrying a translocation t(8;21)(q22;q22); 23 female and 28 male patients. The complete remission rate was 92 percent and median overall survival was 52.4 months. The median overall survival of female patients was significantly worse than of male patients (37.2 months vs not reached, P = 0.025). Additional chromosome aberrations were detected in 41 patients at diagnosis (80 percent), 31 (61 percent) had lost a sex chromosome, seven (14 percent) showed a partial deletion of the long arm of chromosome 9 and in three patients (6 percent) a gain of chromosome 8 was observed. Whereas the loss of a sex chromosome had no influence on prognosis, a partial deletion of the long arm of chromosome 9 was an unfavorable prognostic factor. The median overall survival of the seven patients with del(9q) was only 12.5 months and thus significantly shorter than in patients with only t(8;21) or with t(8;21) and additional sex chromosome loss (median survival not reached: P = 0.0010).     

Familial C/D translocation t(9;13)(9p23.13q21) in a male associated with recurrent abortion

A familial reciprocal translocation, established by R-banding as t(9;13) (9p23;13q21), is described in a phenotypically normal male carrier, whose father is also a balanced carrier and wife had four consecutive spontaneous abortions. The role of translocation in reproductive failure through production of chromosomally unbalanced gametes or by impairment of the spermatogenesis is briefly discussed.     

Another case of t(17;22)(q22;q13) in an infantile dermatofibrosarcoma protuberans

We have identified a new dermatofibrosarcoma protuberans (DP) case with a t(17;22) (q22;q13) occurring in a child. The translocation was substantiated by the presence of one or two copies of the sole der(22)t(17;22). This rearrangement added to two normal chromosomes 17 and one or two chromosomes 22, resulted in trisomy 22cen-q13 and trisomy (or tetrasomy) 17q22-25. This observation confirms the specificity of the association of DP with the t(17;22) found together with extra copies of the der(22)t(17;22). It also points out a possible prevalence of translocation rather than rings in DP of the childhood disease.     

Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23)

We describe two new human leukemia cell lines, MOLM-13 and MOLM-14, established from the peripheral blood of a patient at relapse of acute monocytic leukemia, FAB M5a, which had evolved from myelodysplastic syndrome (MDS). Both cell lines express monocyte-specific esterase (MSE) and MLL-AF9 fusion mRNA. Gene fusion is associated with a minute chromosomal insertion, ins(11;9)(q23;p22p23). MOLM-13 and MOLM-14 are the first cell lines with, and represent the third reported case of, MLL gene rearrangement arising via chromosomal insertion. Both cell lines carry trisomy 8 which was also present during the MDS phase, as well as the most frequent trisomies associated with t(9;11), ie, +6, +13, +19 variously present in different subclones. Despite having these features in common, differences in antigen expression were noted between the two cell lines: that of MOLM-13 being CD34+, CD13-, CD14-, CD15+, CD33+; whereas MOLM-14 was CD4+, CD13+, CD14+, CD15+, CD33+. Differentiation to macrophage-like morphology could be induced in both cell lines after stimulation with INF-gamma alone, or in combination with TNF-alpha, which treatment also induced or upregulated, expression of certain myelomonocyte-associated antigens, including CD13, CD14, CD15, CD64, CD65 and CD87. Together, these data confirm that both cell lines are likely to be novel in vitro models for studying monocytic differentiation and leukemogenesis.     

Cytogenetic analysis of spermatozoa in the father of a child with a de-novo reciprocal translocation t(7;9) (q22;p23)

Analysis of sperm chromosomes was carried out in the father of a child with a de-novo reciprocal translocation t(7;9) (q22;p23) by G-banding and chromosome painting. Sperm metaphases were obtained using the zona-free hamster oocyte-human sperm fusion technique. A total of 138 complements were sequentially analysed by G-banding and fluorescence in-situ hybridization (FISH). The frequency of spermatozoa with structural chromosome abnormalities (5.1%) and the estimated conservative aneuploidy (1.4%) were within the range obtained in our control donors (6.9 and 4%). The sex ratio (45.3% X versus 54.7% Y) was not significantly different from the theoretical 1:1. A total of 309 sperm complements was analysed by FISH, 138 sequentially analysed by G-banding-FISH and another 171 analysed by FISH only. The frequencies of structural chromosome abnormalities for chromosomes 7 and 9 (0.6 and 0% respectively) were not significantly different from those obtained in our control donors (0.6 and 0.8%). No spermatozoa with the t(7;9) (q22;p23) were observed, showing no evidence for a germ-cell mosaicism. A statistically significant, positive association between sperm breakpoints and fragile sites (P = 0.0225) was observed. However, the coincidence between fragile sites and sperm breaks (80%) was not significantly different from that obtained in our control donors (79.2%). These results suggest that in this case the risk of structural chromosome abnormalities in further offspring is not increased, although an association between fragile sites and sperm chromosome breaks in the father does exist.     

Structural aberrations of the long arm of chromosome no. 22. Report fo a family with translocation t(11;22) (q25;q11)

A chromosomal translocation t(11;22) (q25q11) is described in a family. Four members, in two generations, had the same translocation but showed phenotypic variation. Case reports of chromosome aberrations involving the long arm of chromosome 22 associated with and without chronic myeloid leukemia (CML) are reviewed. It appears that the distal segment of the long arm or chromosome 22 is either translocated or deleted, resulting in congenital anomalies, presumably due to chromosome imbalance. In other instances, a specific breakpoint on 22q results in the origin of Philadelphia chromosome (Ph1) associated with CML.