A. Hagemeijer

The clinical significance of karyotype in acute myelogenous leukemia.

To evaluate further the prognostic significance of karyotype at diagnosis of acute myelogenous leukemia (AML), we have made a follow-up study of 711 patients who were diagnosed between January 1, 1980, and March 31, 1982, and who were originally reported by the Fourth International Workshop on Chromosomes in Leukemia (4IWCL). Three different chromosomal classifications were evaluated, including presence of normal and abnormal metaphases (NN-AN-AA classification), a modification of the Chicago classification, and a complexity classification. All three chromosomal classifications were shown to correlate significantly with outcome in patients with de novo AML. Furthermore, the NN-AN-AA classification and the complexity classification had independent prognostic significance when age, sex, and FAB morphology were also considered in multivariate analyses of survival. These data provide further evidence that karyotype is an important factor in predicting the outcome of patients with AML.

Long-term survival in acute myelogenous leukemia: A Second Follow-up of the Fourth International Workshop on Chromosomes in Leukemia

Patients with acute myeloid leukemia (AML, equivalent to acute non-lymphoblastic leukemia [ANLL]) who were studied at the Fourth and Sixth International Workshops on Chromosomes in Leukemia and who have long survival have been re-assessed to identify factors which may be associated with good prognosis in AML. In a long-term survivor (LTS) group, there were more cases than expected in each age decade below 50, more cases than expected with FAB type M3, and fewer cases than expected of secondary leukemia. Of the distribution of chromosome abnormalities, t(15;17), t(8;21), and inv/del(16) were over-represented, and -5, -7, and rearrangements of 11q were under-represented. Multivariate analysis of all patients showed that age group, cytogenetic classification, FAB type, and sex all had independent, significant effects on survival. A new observation from a very small subgroup of patients was that deletion of 7q without concurrent abnormality of chromosome 5 appeared to be associated with a good prognosis.

FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations

The transcription factor Forkhead box protein P1 (FOXP1) is highly expressed in a proportion of diffuse large B-cell lymphoma (DLBCL). In this report, we provide cytogenetic and fluorescence in situ hybridization (FISH) data showing that FOXP1 (3p13) is recurrently targeted by chromosome translocations. The genomic rearrangement of FOXP1 was identified by FISH in three cases with a t(3;14)(p13;q32) involving the immunoglobulin heavy chain (IGH) locus, and in one case with a variant t(2;3) affecting sequences at 2q36. These aberrations were associated with strong expression of FOXP1 protein in tumor cells, as demonstrated by immunohistochemistry (IHC). The cases with t(3p13) were diagnosed as DLBCL ( × 1), gastric MALT lymphoma ( × 1) and B-cell non-Hodgkins lymphoma, not otherwise specified ( × 2). Further IHC and FISH studies performed on 98 cases of DLBCL and 93 cases of extranodal marginal zone lymphoma showed a high expression of FOXP1 in approximately 13 and 12% of cases, respectively. None of these cases showed, however, FOXP1 rearrangements by FISH. However, over-representation of the FOXP1 locus found in one additional case of DLBCL may represent another potential mechanism underlying an increased expression of this gene.

Translocation (9;11)(p21;q23) in three cases of acute monoblastic leukemia

Abstract A balanced translocation t(9;11)(p21;q23) was found in three cases of acute monoblastic leukemia (AMol or M5 according to the FAB classification). This translocation, which involves small chromosomal segments of approximately the same length, is difficult to recognize with certainty when techniques other than R-bands are used. A new specific association is proposed between this translocation and acute leukemia of the M5 type.

Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization

Marginal zone B cell lymphoma (MZBCL) represents a distinct subtype of B cell non-Hodgkin’s lymphoma, which has been recently recognized and defined as a disease entity. We investigated 25 cases (18 at primary diagnosis and seven during the course of disease) of MZBCL by comparative genomic hybridization (CGH) and compared these results with cytogenetic, fluorescence in situ hybridization (FISH), and Southern blot data. Twenty of the 25 cases (80%) showed gains (total 49) or losses (total 15) of genetic material. In extranodal, nodal, and splenic MZBCL, material of chromosomes 3 (52% of cases), 18 (32%), X (24%), and 1q (16%) was most frequently gained, whereas losses predominantly involved chromosomes 17 (16%) and 9 (12%). High-level amplifications involving the regions 18q21-23 and 18q21-22, respectively, were detected in two cases. Gains of chromosomes 1q and 8q and losses of chromosome 17 or 17p occurred more frequently in relapsed or progressive lymphomas. For all of the frequently affected chromosomes, CGH allowed narrowing of the relevant subregions including 3q21-23, 3q25-29 and 18q21-23. By Southern blot analysis, the BCL2, BCL6, and CMYC proto-oncogenes were found to be a part of the over-represented regions in two cases, one case, and two cases, respectively, with gains involving 18q, 3q or 8q. In 13 cases, CGH revealed chromosomal imbalances which were not detected by cytogenetic analysis but could be confirmed by FISH or Southern blot analysis in all cases investigated. On the other hand, CGH failed to detect trisomy 3, trisomy 18, and deletion 7q in three cases with a low proportion of tumor cells bearing these abnormalities, as shown by interphase FISH. The characteristic pattern of chromosomal gains and losses detected in this study confirms the distinct nature of MZBCL and may point to chromosomal regions involved in the pathogenesis of these neoplasms.

Cytogenetic analysis of malignant mesothelioma

Cytogenetic analyses of 40 confirmed malignant mesotheliomas (MMs) are reported. Pleural effusion cells were studied in 90% of the cases by direct method or after culture or both. Biopsy and ascites fluid were also analyzed in some patients. A normal karyotype was found in nine cases, and complex karyotypic abnormalities were observed in 30 cases. In one case, analyzable metaphases were not obtained. The chromosomal changes were all complex and heterogeneous; no consistent presumably specific abnormality was detected. Nevertheless, two main patterns of nonrandom abnormalities were observed: 1) loss of chromosomes 4 and 22, 9p, and 3p in the most of the abnormal cases and corresponding to a hypodiploid and/or hypotetraploid modal chromosome number; and 2) gain of chromosomes 7, 5, and 20 with deletion or rearrangement of 3p as well in the hyperdiploid cases, which were a minority in our series. These findings are discussed in view of other reported cytogenetic studies of MM, asbestos exposure, and possible mechanisms of malignant transformation.

Replication pattern of the X chromosomes in three X/autosomal translocations

Three X/autosomal translocations, two familial and one de novo, were analyzed. Late-replicating chromosomes and chromosome regions were studied with R-banding techniques after BrdU incorporation. The first translocation, t(X;4)(q21;q13), was a de novo translocation, found in a woman with amenorrhea. The structurally normal X was late replicating in all cells. The second translocation, t(X;6)(p21;q26), was found in an unbalanced form, 46,XX,der(6), in a phenotypically abnormal girl; her mother carried the balanced translocation. In the mothers blood culture inactivation of the Xs followed two modes: In 85% of the cells the normal X was late replicating, and in the remaining 15% the der(X) was inactivated, including the attached fragment of chromosome 6. The third translocation, t(X;17)(p11;q24), was found in three generations. In the phenotypically normal mother, who carried the balanced translocation, the late-replicating X was always the normal X. In her daughters, who had an unbalanced karyotype, 46,X,der(X), and multiple congenital abnormalities, the X part of the translocation chromosome was always late replicating. No spreading of inactivation over the attached autosomal region was observed, resulting for these patients in a partial trisomy of 17q. Their peculiar phenotype is described.

Localization of genes on human chromosomes by studies of human-Chinese hamster somatic cell hybrids

SummaryAbout 75 man-Chinese hamster hybrid clones were analysed for their human chromosome complement and simultaneously tested for human enzyme markers. Correlation of the presence of chromosomes and enzyme activity revealed assignments of the PGD linkage group to chromosome 1, ME1, PGM3 and IPO-B to 6, LDH-A to 11, LDH-B to 12 and IPO-A to 21.The assignment of PGM3 puts the HL-A loci on chromosome 6. Segregation of the enzymes of the PGD linkage group was demonstrated in a clone which had retained a deleted chromosome 1. Subclones of this line indicate that the loci for PGD and PGM1 are situated on the short arm or proximal part of the long arm of 1 and the locus for Pep-C on the long arm.ZusammenfassungEtwa 75 Hybrid-Zellklone Mensch/Chinesischer Hamster wurden in bezug auf den menschlichen Anteil ihres Chromosomensatzes analysiert und gleichzeitig auf menschliche Enzym-Marker untersucht. Die Korrelation zwischen Anwesenheit von Chromosomen und Enzym-Markern ließ die Folgerung zu, daß die PGD-Koppelungsgruppe auf Chromosom 1, ME1, PGM3 und IPO-B auf Nr. 6, LDH-A auf 11, LDH-B auf 12 und IPO-A auf Chromosom 21 gelegen ist.Die Lokalisation von PGM3 läßt die Folgerung zu, daß auch die HL-A-loci auf Chromosom 6 lokalisiert sind. Aufspaltung der Enzyme der PGD-Koppelungsgruppe konnte an einem Klon dargestellt werden, der ein deletiertes Chromosom 1 enthielt. Die Subklone dieser Linie zeigen, daß die loci für PGD und PGM1 auf dem kurzen Arm oder dem proximalen Teil des langen Arms von Chromosom Nr. 1 liegen, während der locus für Pep-C auf dem langen Arm gelegen ist.

Partial trisomy 21

SummaryCytogenetic analysis of a 6-year-old girl with moderate mental retardation revealed 46 chromosomes with a tandem translocation (21;21) resulting in a partial trisomy 21. Only the terminal band 21q22 was not in triplicate. G-, Q-, R-, and C-banding techniques and silver nitrate staining of the nucleolus organizer regions (NORs) were used to identify this chromosome fully.The phenotype of the patient was not typical for Downs syndrome, providing additional evidence that trisomy of band 21q22 is pathogenetic for the phenotype of Downs syndrome. This is also a new example in human pathology of a stable ‘dicentric’ chromosome in which one of the centromeric constrictions appears to be nonfunctional.

Hyaline vascular Castleman's disease with HMGIC rearrangement in follicular dendritic cells: molecular evidence of mesenchymal tumorigenesis.

Chromosomal aberrations involving chromosome segment 12q13-15 are a common finding in a variety of benign mesenchymal tumors. The target gene encodes for HMGIC, a member of the high mobility group protein family. These proteins act as architectural transcription factors. HMGIC plays a role as a common genetic denominator in benign mesenchymal tumorigenesis. We report a case of hyaline vascular Castlemans disease with intragenic HMGIC rearrangement, due to a clonal cytogenetic aberration involving the long arm of chromosome 12 [46,XX, add(1)(q21),der(6)t(6;12) (q23;q15),add(7)(p22), -9,inv(9)(p11q13),del(12)(q15),+mar] obtained after short-term primary cultures. A combined immunocytologic-cytogenetic approach enabled us to demonstrate the exclusive presence of HMGIC rearrangement in anti-CD21 reactive follicular dendric cells. This finding confirms that a clonal proliferation of follicular dendritic cells occurs in the hyaline vascular variant of Castlemans disease. It also provides a possible molecular pathway explaining stromal overgrowths and stromal neoplasms developing from this disorder.