Association of GP40/CD7+ acute myeloblastic leukemia and chromosome 5 aberrations.
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Biomedical subjects
Publications and source records attributed to H Nowotny.
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Trisomy 4 as single karyotype anomaly has recently been proposed as an acute myeloid leukemia (AML) specific aberration. Up to now, 20 cases have been reported in which the single abnormality occurred without additional chromosomal aberrations. Trisomy 4 has been found in both primary and secondary AML, the majority of cases being diagnosed as FAB M4 or M2 subtypes. In the cytogenetic analysis of 305 patients with AML, we found 209 cases with aberrant karyotypes, among them two patients (22a, male, M2; and 69a, male, M4) with trisomy 4 as single aberration. The younger patient achieved complete remission lasting 13 months and survived 22 months whereas the older patient died in aplastic phase due to septicaemia 5 weeks after admission. Trisomy 4 is proposed to be the primary aberration in both these cases of de novo AML. Although in one case, as in two cases reported earlier, cytogenetic results were only available in first relapse, we have no indication that trisomy 4 appeared in a secondary induced leukemia, because the leukemic blasts of the relapse were morphologically identical to first acute phase. In contrast to other specific chromosomal aberrations, results indicate that trisomy 4 has as yet no prognostic relevance concerning the clinical outcome.
In an attempt to confirm the existence of acute myeloid leukemia (AML) with trisomy 22, we studied three patients in whom trisomy 22 imposed as the sole karyotype abnormality. After revision of the karyotypes, however, we were able to identify an inv(16) as the important primary abnormality in all of them. Based on this experience, we investigated whether at least some of the 17 AML cases with trisomy 22 reported so far might possibly have been misinterpreted. Interestingly, ten out of 16 evaluable cases were classified as M4, some of them with bone marrow eosinophilia. As in cases with inv(16), only few metaphases contained trisomy 22. Furthermore, in at least two out of the only four published karyotypes of cases with trisomy 22, an inv(16) is evident and in the other two cases it cannot be ruled out. We therefore believe that at least some of the trisomy 22 cases mentioned in the literature are in fact only secondary changes occurring in AML with an inv(16) and suggest that future reports of AML with trisomy 22 as a specific primary abnormality can only be accepted as such if inv(16) has been excluded with appropriate methods.
Methodological prerequisites for the culture of leukaemic blasts and the fluorescence banding of spread metaphases are represented in detail. By using an improved method the percentage of aneuploid karyotype findings increased in AML from 49% to 68% and ALL from 65% to 81% of all evaluable patients. Specific aberrations known up to the present day are discussed. They could be diagnosed in 46% of aneuploid AML-clones and in 59% of ALL-clones. The fluorescence banding according to the three-colour technique is demonstrated by three examples of "non-specific" aberrations: a) Tandem translocation of 1q and 7 q (64a, male, FAB:M5B), b) Karyotype instability with variability of chromosome numbers arising from trisomy, tetrasomy and polyploidisation of single normal as well as marker chromosomes (57a, female, FAB:M6), c) Identification of a marker chromosome as a derivative chromosome 16 (33a, female, FAB:L2, c-ALL).
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Three new human myeloma cell lines (U-1957, U-1958, and U-1996) have been established in vitro. The cell lines are Epstein-Barr virus (EBV) negative, monoclonal, and aneuploid and should thus represent malignant cell populations and not EBV-carrying non-neoplastic B lymphoblastoid cell lines. The myeloma origin of the cell lines is also suggested by their capacity for production of monoclonal complete immunoglobulin (Ig) molecules (U-1957 and U-1958) or IgG light chains (U-1996) of the same type as the myeloma protein in vivo. All the cell lines have morphological features of plasmablasts-plasma cells but appear to represent slightly different stages of B cell differentiation. Thus, the U-1958 has plasma cell morphology, expresses only PCA-1 and OKT-10 but no other B cell antigens, and secretes 1.5 micrograms/mL of IgG/10(6) cells/24 hours. The U-1957 has plasma cell morphology and expresses Fc receptors and the LB-1 antigen in addition to the PCA-1 and OKT-10 antigens. This line produces only minimal amounts of IgG, which appears not to be secreted. The U-1996, finally, is a kappa light chain producer, has a plasmablast morphology, and expresses LB-1 in addition to the PCA-1 and OKT-10 antigens. All three cell lines are chromosomally heterogeneous and contain several markers with a 14q+ abnormality as a common characteristic abnormality. These new myeloma lines have been in continuous culture for approximately 3 years and are instrumental in studies of various aspects of the biology of human myeloma.
Chromosome studies of a case of erythroleukemia in a 57-year-old female patient were made from bone marrow aspirates using the fluorescent primary stain/counterstain methodology. The chromosome number ranged from 42 to 110. There was a high proportion of hypotetraploid cells and a few hypertetraploid and hypooctaploid ones. Structurally normal chromosomes varied in number from cell to cell, ranging from one to seven in the polyploid cells. A number of marker chromosomes were observed, some of which occurred repeatedly in two copies per hypotetraploid cell. The chromosomes involved in aberrations were tentatively identified as #3, #5, #7, #12, #13, #15, #16, #18, #19, and #21. In the abnormal chromosome #16, which was missing a normal short arm, a new kind of heterochromatin was demonstrated by sequential staining with DA-DAPI and DAPI-AMD, suggesting de novo amplification of an A-T-rich satellite DNA sequence.
111 adults with acute myeloid leukemia were classified according to the morphological, immunological and cytogenetic features of their leukemic cells. A comparison was made between the clinical parameters on prognosis of these subgroups. Hemoglobin was the only parameter among all six FAB-subgroups to show a statistical significant difference. Other differences found applied to a few subgroups only. Again, immunologically or cytogenetically characterized subgroups did not show significant differences in clinical parameters or prognosis. Patients with pseudodiploid or hyperdiploid karyotype had a lower remission rate than the remainder. However, a cluster analysis in which all three classifications together with the clinical parameters were considered was best able to characterize groups with different prognosis.
Karyotype analysis using the Tri-staining-technique (Chromomycin A3/Distamycin A/DAPI) and subsequent DAPI/AMD staining (Schweizer, 1981) was performed on the bone marrow and peripheral blood of three patients with "Burkitt-like" acute lymphatic leukaemia (FAB: L3). In two patients we found the specific translocation t(8;22). One patient displayed in addition a structural abnormality of chromosome 9, visualized with C-banding using the DA/DAPI stain, and in two patients we found specific abnormalities of chromosome 1. Several patterns of the abnormal chromosome 1 revealed an intercalated DA/DAPI positive C-band in the elongated long arm.
72 patients were diagnosed as suffering from myelodysplastic syndromes (MDS) according to the FAB classification: 16 patients with refractory anaemia (RA), 11 patients with acquired idiopathic sideroblastic anaemia (AISA), 14 patients with refractory anaemia with an excess of blast cells (RAEB), 7 patients with RAEB in transformation (RAEB/t) and 24 patients with chronic myelomonocytic leukaemia (CMML). The duration of the preleukaemic phase was between 2 and 189 months (median: 15 months); RAEB in transformation and CMML showed a median phase of less than 12 months. Transformation into acute leukaemia (AL) occurred in 46 patients (64%). Of the clinical signs only thrombocytopenia was a significant poor prognostic factor (p less than 0.01). Cytogenetic studies were made in 31 patients. 14 had clonal aneuploidy: these patients had a higher risk of AL, but not a significantly shorter preleukaemic phase (p greater than 0.1). Stem cell cultures (CFUc) were carried out in 31 patients. Patients without colony growth or only cluster growth showed a high incidence (10/11 and 8/8) of transformation into AL; preleukaemic phases were significantly shorter than in patients with normal colony growth or cluster + colony growth in all FAB subgroups (p less than 0.001). The bone marrow blast cell count was indirectly proportional to the duration of the preleukaemic phase: thrombocytopenia, cytogenic aberrations and failure of in vitro colony growth are additional poor prognostic factors in MDS.
So-called "Philadelphia-positive acute leukaemias" require varied therapeutic management. Additional chromosome anomalies together with Ph1 indicate an acute transformation of a Philadelphia-positive disease, requiring "non-myelotoxic" treatment and new therapeutic approaches. By contrast, "de novo" acute leukaemias with a Ph1-positive karyotype should be treated with intensive chemotherapy for the induction and maintainance of remission.
The significance of morphology and the number of lymphocyte nucleoli was evaluated by electronmicroscopic sections of malignant lymphomas. It was not only the number and the size of nucleoli which characterized malignant lymphomas differing in histological respect, but above all the different morphology of the nucleoli. The prognostic significance of the nucleolus can be illustrated, if malignant lymphomas of a low grade malignancy with a preponderance of micronucleoli and a low nucleolar index are compared with a significantly higher nucleolar index and markedly increased macronucleoli. These differences are further supplemented by additional morphological properties of nucleoli in malignant lymphomas.
Chromosomal and isoenzyme alteration of a human leukemia cell line, REH6, is shown during 80 subsequent passages. No correlation between these properties could be found.
Three patients with eosinophilic leukemia and atypical granulation in the eosinophils are described. A remarkable light and electron microscopic finding was the appearance of enormous granules in the neurtophils and eosinophils. In addition the usual anomalies seen in acute leukemia, for example asynchronisation in cell maturation, fibrillar bundles, shrinkage of nucleolus and cell organelles, signs of degeneration and also the auer-rods characteristic of AML are observed.
A case of acute lymphoblastic leukemia (ALL), in a 50 years old patient, 26 years after thorotrast injection, is reported. In spite of intensive therapy, he died 2 years after diagnosis of disease. The cytogenetic showed the usual thorotrast radiation-induced abnormalities, although to a greater extent than reported in leterature. Furthermore a hypodiploidy was present, which was connected with ALL. In addition the patient exhibited the interesting phenomenon of giant satellites on one of his D14-chromosomes. This abnormally was found also in his mother and son. The question arises, how far the inherited cytogenetic pattern and the thorotrast radiation each contributed to the development of ALL.
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