Philadelphia chromosome in human multiple myeloma.

Four patients with multiple myeloma in whom a Ph1 chromosome was found were described; 1 patient had a (9;22) translocation, 2 had no evidence of a translocation, and 1 had a complex translocation (3;8;22). Ph1 chromosomes with standard (9;22) or with unusual translocations were recently found in various myeloproliferative disorders (other than chronic myelogenous leukemia) and in acute lymphoblastic leukemia. These findings point to the genesis of a Ph1 chromosome in diseases other than chronic myelogenous leukemia and other myeloproliferative disorders.

Cytogenetic analysis of B cell chronic lymphoid leukemias classified according to morphologic and immunophenotypic (FAB) criteria.

609 patients with B cell chronic lymphoproliferative disorder were studied with the primary aim of analyzing the cytogenetic profile of B cell chronic lymphocytic leukemias and, if possible, define correlations with FAB classification of these diseases. Morphological and immunological studies were performed according to criteria proposed by the FAB group. A panel of monoclonal antibodies, including at least sIg, CD19, CD5, and FMC7 was used. Interpretations of morphology and cytogenetics were made independently. When applying strict FAB criteria 65% of the cases could be classified. Most of them (44%) were chronic lymphocytic leukemia (CLL). The cases not satisfying strict FAB criteria could be divided into two groups: one closely related to CLL, and here defined as atypical CLL (aCLL) (21%) and another group consisting of patients with leukemic manifestations of B cell non-Hodgkin's lymphoma (LL) (14%). Analyzable metaphases were obtained in 89% of patients. Clonal abnormalities were present in 35% of patients. The most frequent chromosomal changes were abnormalities of chromosome 11q (60 cases), trisomy 12 (46 cases) and structural rearrangements of chromosome 14q (44 cases). Statistical associations with FAB subtypes were found: aCLL and trisomy 12 (P < 0.00001); mantle zone lymphoma (MZL) and t(11;14) (P < 0.00001) and del(6)(q) (P < 0.0001); CLL/mixed cell type and del(6)(q) (P < 0.002); follicular lymphoma and t(14;18) (P < 0.00001); splenic lymphoma with villous lymphocytes and del(7)(q) (P < 0.0004); leukemic lymphoma (LL) with rearrangements in chromosome 9q (P < 0.0001) and trisomy of 3 (P < 0.001). Chronic lymphocytic leukemia was not statistically associated with any specific chromosomal abnormality. However, this subtype showed a high incidence of del(11)(q) and rearrangements of 13q. This study confirms the value of cytogenetic investigation in the diagnosis of these disorders and may provide some new elements for future refinement of the FAB classification in mature B cell lymphocytic disorders.

5q- anomaly in lymphoid disorders.

Observations made in two patients and a review of the literature confirm the occurrence of a 5q- chromosome anomaly in lymphoproliferative disorders of both T and B cell type. Additional chromosome changes were invariably present and are of the "lymphoid" type. The chromosome morphology of the 5q- is indistinguishable from that found in myeloid disorders.

Association of aberrant transcortin levels with HLA antigens of the B and C loci: high transcortin levels are frequently found in patients with lymphatic leukemia, hairy cell leukemia, or non-Hodgkin lymphoma.

HLA antigen B12 is in linkage disequilibrium with HLA antigen Cw5. In some way this particular haplotype seems to be associated with a mechanism increasing serum transcortin levels. As shown before, the latter mechanism does not involve elevated estrogen levels or a generalized increase in glycoprotein synthesis. Similar high transcortin levels (more than 2 SDs above the mean) are found frequently in patients with lymphatic leukemia, hairy cell leukemia, or non-Hodgkin lymphoma, as well as in the siblings of these patients. HLA antigen Bw35 is in linkage disequilibrium with HLA antigen Cw4. Transcortin levels in patients with this combination of HLA antigens are significantly lower than in patients who do not carry these two antigens. Relatives of subjects with very low transcortin levels often have the same low levels. These findings together with recent data in the literature suggest that a cluster of genes regulating certain aspects of glucocorticoid metabolism is located in the vicinity of HLA locus B and C.

Unexplained high transcortin levels in patients with various hematological disorders and in the relatives: a connection between these high transcortin levels and HLA antigen B12.

Forty-one our of 141 patients with various hematological disorders had serum transcortin values more than 2 sDs above the normal mean (relative risk vs. controls, 10.78). Their relatives also had a higher incidence of unusually high transcortin values. The serum levels of steroid-binding beta-globulin were normal in these patients as well as in their relatives, making an increase in estrogenic impregnation as the cause of the high transcortin levels most improbable. Other known causes of increased transcortin levels could also be excluded. Such unusually high transcortin levels are 4.74 times more frequent in subjects carrying an HLA antigen B12 than in a control group [P (corrected) less than 0.006]. However, the HLA antigen B12 and hematological disorders were independently associated with high transcortin levels.

More HLA haploidentity in pairs of sibs with the same transcortin levels.

In 50 sibships, each comprising at least 2 male sibs, the oldest sib was paired with each of his brothers. All sibs were HLA- haplotyped and their serum transcortin level was determined. The HLA haploidentical pairs were compared with the sibpairs having no HLA haplotype in common. The odds for the haploidentical pairs of having a small difference (less than 0.07 mg per g total serum protein) in serum transcortin was nearly 4 times (3.94; P less than 0.025) greater than for the pairs of brothers having no HLA haplotype in common. This abnormal distribution in HLA haplotypes confirms our previous findings on the relation of certain HLA haplotypes with either high or low basal serum transcortin levels.

Rearrangements of the short arm of chromosome No. 6 in T-cell lymphomas.

Cytogenetic studies on four patients with T-cell lymphomas are reported. In all four the short arm of chromosome No. 6 (6p) was abnormal. In three cases it was involved in a translocation, and in one there was a deletion of the terminal part: del(6)(p23-24). One of the translocations could be identified as a t(2:6)(q24;p24). Identification was not possible in the others. These 6p anomalies were associated with complex structural and numerical abnormalities of other chromosomes in three out of four cases. In three patients chemo- and/or radiotherapy administration preceded cytogenetic investigations.

Cutaneous mastocytosis after autologous bone marrow transplantation.

A 41-year-old male patient developed cutaneous mastocytosis 3 months after autologous bone marrow transplantation (ABMT). The ABMT was performed as part of consolidation treatment for a high-grade malignant non-Hodgkin's lymphoma. There was no evidence for systemic mastocytosis. Recurrence of the lymphoma could not be shown. Mast cell proliferation frequently coexists with dysplastic and neoplastic disorders of myeloid and, more rarely, of lymphoid cells. Mast cells are growth factor responsive and ultimately originate from the pluripotent hematopoietic stem cell. After autologous bone marrow transplantation, hematological reconstitution may in rare cases lead to an abnormal proliferation of mast cells possibly due to unbalanced production of growth factors.

Discordances of cytoplasmic immunoglobulin G staining with the immunoperoxidase technic in plasma cells from bone marrow, tonsils, and appendix.

Plasma cell cytoplasmic immunoglobulin was stained using the peroxidase-antiperoxidase technic in Bouin-fixed, paraffin-embedded human tissues from different origins. Bone marrow (BM), tonsils, and appendices were examined. IgA-, IgD-, and IgM-secreting plasmocytes were easily studied using highly diluted rabbit antihuman antisera in all tissues, including BM. IgG plasmocytes showed good stainability in tonsils and appendices, but variable results were obtained in BM. Bone marrow IgG plasmocytes from persons without infection required a tenfold higher concentration of rabbit antihuman IgG than plasmocytes derived from patients with infection. Stainability of BM plasmocytes from patients with infection was equal to BM plasmocytes from myeloma patients. Because the same rabbit antihuman IgG concentration could be applied for staining plasmocytes derived from tonsils and appendices, it is most probable that the difference in staining ability is due to a difference in activity of the plasmocytes, i.e., a different IgG concentration in the plasmocytes.

Reciprocal translocation t(6;9)(p21;q33): a new characteristic chromosome anomaly in myeloid leukemias.

Three patients with myeloproliferative disorders, two acute myeloid leukemias and one chronic myelocytic leukemia, were found to present a t(6;9)(p21;q33) as the sole anomaly in the leukemic cells. It is likely that this translocation is to be added to the steadily growing list of characteristic chromosome changes in human malignancy.

Cytogenetic studies in T-cell malignancies.

Clonal chromosome abnormalities in ten cases of T-cell lymphoproliferative disorders are reported. In addition, an extensive review of the literature on T-cell lymphomas shows the chromosomal sites most frequently involved in structural rearrangements.

The short arm of chromosome 6 is nonrandomly rearranged in secondary myelodysplastic syndromes.

Eight patients with a myelodysplastic syndrome showed a structural rearrangement of the short arm of chromosome #6 involving the distal segment 6p22----6pter. In four cases the myelodysplastic disorder appeared after treatment with chemo- and/or radiotherapy. Cytogenetically, the 6p anomaly was consistently associated with abnormalities of chromosome #5 and/or #7 in seven of eight cases. We believe we identified a new site on 6p that is nonrandomly involved in iatrogenically and possibly also environmentally induced malignant hematologic disorders.

Variant translocation t(15q;17q) accompanying a promyelocytic accelerated phase of Ph-positive chronic myeloid leukemia.

One case of Philadelphia-positive chronic myeloid leukemia showed a high promyelocytic component associated with a variant t(15q-,17q+) translocation. A key role for chromosome #17 in the promyelocytic proliferation and/or differentiation is emphasized.

High incidence of chromosome abnormalities in IgG3 myeloma.

Chromosomes were studied in 33 untreated myeloma patients, and results were correlated with the class of Ig secreted by the myeloma cells. A high incidence of clonal karyotypic anomalies seemed to be present in IgG3 myeloma patients, in whom the disease was advanced at diagnosis and rapidly progressing. Among the chromosome anomalies, the t(11;14)(q14;q32) was particularly prominent, and this chromosome anomaly, in analogy with the Ph1 chromosome, may characterize a family of lymphoproliferative disorders.

A chromosomal profile of polycythemia vera.

One hundred four patients with a diagnosis of polycythemia vera and a variable period of follow-up had one or more cytogenetic investigations. Chromosome abnormalities were found in 13% of untreated patients, in 56% of cases treated with radioactive phosphorus (32P) or cytotoxic drugs, and in 85% of patients in which transformation of the disease had occurred. Nonrandom chromosome abnormalities found before treatment included +8, +9, 13q-, 20q-; their prognostic value is little, as they are often associated with longstanding, stable disease. In contrast, 5q- anomaly and the appearance of subclones in patients with an abnormal karyotype were found to be poor prognostic signs, as they are usually coincidental with evolution of the disease to myelofibrosis or leukemia. Chromosomally two patterns of acute leukemia were observed in polycythemia vera patients. The first type resembles de novo acute leukemia, in that the clinical and cytologic characteristics of the disorder are easily defined by FAB criteria and the chromosome changes compatible with the types usually found in those conditions. In the second type, assignment to a FAB morphologic subgroup was more difficult, myelodysplastic changes were often present, and the karyotype showed complex abnormalities frequently involving chromosomes #5 and #7. All these features suggest the occurrence of secondary leukemia.

Cytogenetic and clinical investigations in 76 cases with therapy-related leukemia and myelodysplastic syndrome.

Clinical, cytomorphologic, and cytogenetic investigations were carried out in a series of 76 secondary MDS and ANLL. Chromosome abnormalities were more frequent in patients with a history of multiple myeloma or macroglobulinemia (92%) and myeloproliferative disorders (82%) than in patients with previous breast cancer (40%). The secondary hematologic malignancies were mostly a trilineage bone marrow disorder. The most commonly found cytogenetic anomaly was monosomy 7, followed by total or partial loss of chromosome 5. In addition six other chromosomes, i.e., chromosome 3, 8, 9, 12, 17, and 21 seemed to be consistently involved in the pathogenetic mechanisms of secondary leukemia and MDS.

11q-chromosome is associated with abnormal iron stores in myelodysplastic syndromes.

Nine cases of myelodysplastic syndrome with a deletion of the long arm of chromosome #11 (11q-) showed ringed sideroblasts, and three of which had an acquired sideroblastic anemia according to the criteria of the FAB classification. In contrast, among four cases of myelodysplastic syndromes with translocation of extra material to the long arm of chromosome #11 (11q+), only one showed bone marrow sideroblasts. These results strongly indicate that an 11q- chromosome is a marker of iron overload in myelodysplastic syndromes. Within the cases of 11q- associated with sideroblastosis, two cytogenetically different anomalies (i.e., terminal or interstitial deletions) were delineated.

3q-, 3q+ anomaly in malignant proliferations in humans.

Anomalies of both No. 3 chromosomes, of the t(3q-; 3q+) type can be observed in human malignancy as reported previously. It is our experience that this anomaly is found predominantly in myeloproliferative disorders, as a rather rare event, though occurring more frequently than similar exchanges between other homologous chromosomes. Previous claims about a relationship between this anomaly and thrombocytosis could not be confirmed, but the features found in a few patients indicate that further research should be undertaken to clarify this point.

Translocation t(6;9) occurring in acute myelofibrosis, myelodysplastic syndrome, and acute nonlymphocytic leukemia suggests multipotent stem cell involvement.

The cytological and cytogenetic features of six patients with myeloid neoplasia and t(6;9)(p23;q34) including a case of acute myelofibrosis (AMF), a refractory anemia with excess of blasts (RAEB), and four cases of acute nonlymphocytic leukemia (ANLL) are described. Two patients in this series, both affected by ANLL type M2, presented an increase of bone marrow basophils, suggesting that this cytological-cytogenetic association is not absolute and that it may be more frequently observed in ANLL with maturation. All patients with de novo ANLL showed associated myelodysplastic features, and one patient presented a dysmyelopoietic syndrome, later evolving into ANLL. The presence of the t(6;9) in a range of myeloid neoplasias, with either concurrent myelodysplastic features or a preleukemic phase in cases of ANLL, provide evidence that this chromosome aberration may always involve a multipotent myeloid stem cell. Data on toxic exposure of the patients suggests that myeloproliferative disorders with the t(6;9) may frequently represent environmentally induced neoplasias.

Philadelphia-positive T-acute lymphoblastic leukemia.

A case of typical T-acute lymphoblastic leukemia (T-ALL) is reported in which, at diagnosis, 100% of bone marrow metaphases showed a Philadelphia (Ph) translocation, t(9;22). These cells completely disappeared following chemotherapy. The significance of the Ph chromosome in T and B leukemic cells is discussed.