Biological implications of consistent chromosome rearrangements in leukemia and lymphoma.
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Acute Disease↗
Biomedical subjects
J D Rowley
Publications and source records attributed to J D Rowley.
Cytogenetic studies on patients with chronic T cell leukemia/lymphoma.
Cytogenetic studies were performed on three patients with chronic T cell leukemia and on one patient with T cell lymphoma. One of the patients had leukemic cells derived from a suppressor T cell clone, another expressed OKT3, 4, and 8, and cells of the other two were derived from a helper T cell clone. All patients had an abnormal karyotype in peripheral blood or bone marrow cultured with or without mitogen. Modal chromosome numbers were 42 and 44/45 in one patient each and 47 in the 2 others. The structural and numerical abnormalities involved almost all chromosomes, except no. 19 and the X chromosome. All patients had a rearrangement of the long arm of no. 14, with a break at band 14q11;3 patients also had a break at 14q32. An inversion of 14q occurred in two patients; a tandem translocation involving both no. 14 chromosomes and a translocation between no. 14 and no. 17 each occurred in one patient. The break in 14q at band q11 in our cases resembles the chromosome change reported in ataxia telangiectasia. This provides added support for the proposal that a 14q rearrangement involving band q11-12, with or without an accompanying break in 14q32, may confer a proliferative advantage on lymphocytes, especially on those of T cell origin.
Aged↗
Prognostic implications of karyotype and morphology in patients with non-Hodgkin's lymphoma.
Clonal chromosome abnormalities were observed in 30 patients with non-Hodgkin's lymphoma; the type of lymphoma was characterized on the basis of the International Working Formulation. The 30 patients were classified into five groups according to the chromosome abnormality. There were 8 patients with t(14;18), 3 with t(8;14), 7 with a translocation to the long arm of chromosome 3 (a 3q+ chromosome), 5 with near-tetraploidy, and 7 with other abnormalities. Among the 8 patients with t(14;18), 5 had follicular small cleaved-cell lymphoma (FSC), I had follicular mixed cell lymphoma (FM), and 2 had diffuse large-cell lymphoma (DL); the diagnosis in these 2 patients was based on extranodal tissue. All 3 patients with t(8;14) had DL and B-cell markers. Except for 1 patient, all those with a 3q+ chromosome had DL; 4 of those who were tested had B-cell or pre-B-cell markers. Four of the 5 patients with near-tetraploidy had follicular mixed-cell lymphoma, and 2 of the 7 patients with other abnormalities had T-cell lymphoma. Thus, patients with a t(8;14), a 14q+ chromosome, or a 3q+ chromosome all tend to have diffuse large-cell lymphoma, usually of the non-cleaved type. On the other hand, our data suggest that patients with FSC generally have a t(14;18) whereas those with follicular and diffuse mixed small cleaved cells and large noncleaved cells have a different pattern with modal chromosome numbers in the tetraploid range. We added 17 previously reported patients to the 30 presented here and correlated the karyotype with survival. The 6 patients with near-tetraploidy had the longest median survival, 69 months, the 15 patients with t(14;18) had the next longest, 48 months. The 4 patients with t(8;14) had the shortest survival, 12 months, and the 9 with other abnormalities had the next shortest, 17 months. Intermediate survivals of 27 and 30 months were observed in patients with a 14q+ or a 3q+ chromosome, respectively. The median survival of these various categories differs and our data, thus, indicate that the karyotypic pattern of the malignant cell may be a significant independent prognostic feature influencing the survival of patients with non-Hodgkin's lymphoma.
Adult↗
Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association.
We identified 18 patients with an inversion of chromosome 16, inv(16)(p13q22), among 308 patients with newly diagnosed acute nonlymphocytic leukemia. Each of these 18 patients had acute myelomonocytic leukemia (M4 subtype) and eosinophils with distinctly abnormal morphology, cytochemical staining, and ultrastructure. These eosinophils constituted from 1 to 33 per cent of the nucleated marrow cells. In our series, every patient with acute myelomonocytic leukemia and abnormal eosinophils also had an abnormal chromosome 16. This subgroup of M4 patients had a good response to intensive therapy designed to induce remission; 13 of 17 treated patients entered a complete remission, and 10 remain in first remission. Thus, patients with an inversion of chromosome 16 appear to represent a unique cytogenetic-clinicopathological subtype of acute nonlymphocytic leukemia with a favorable prognosis.
Adolescent↗
Human oncogene locations and chromosome aberrations.
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Animals↗
Correlation of in vitro culture pattern and Q-banded karyotype in acute nonlymphocytic leukemia.
Both cytogenetic abnormalities and in vitro growth patterns of leukemic cells have prognostic significance in acute nonlymphocytic leukemia (ANLL). The present study was undertaken to analyze the interrelationship between these two factors and response to therapy. Blast cells from 43 patients with de novo ANLL, four patients with secondary ANLL, and two patients with ANLL following a preleukemic phase were studied using both in vitro culture in methylcellulose and quinacrine chromosome banding techniques. In 19 patients with de novo ANLL, minimal growth in culture (less than or equal to 5 colonies without prominence of small clusters) was noted (Pattern I). Blast cells from the remaining 24 patients formed numerous abnormal clusters and colonies in a continuum distribution (Pattern II). Sixty-three percent of Pattern I patients had completely normal karyotypes (NN). Only 29% of Pattern II patients were NN. No Pattern I patient had only abnormal karyotypes (AA), while 25% of Pattern II patients were AA (p less than 0.05). All six patients with secondary leukemia or leukemia following a preleukemic phase demonstrated both Pattern II growth and cytogenetic abnormalities. Fifty-six percent of Pattern I patients with de novo ANLL responded to chemotherapy, 35% of Pattern II patients responded, and 0% of patients with secondary or post-preleukemic ANLL responded. The correlation between the presence of cytogenetic abnormalities in leukemic cells and a pattern of excessive, abnormal growth in vitro coupled with the trend toward poor prognosis in these patients suggests that cytogenetically abnormal cells may have a proliferative advantage both in vitro and in vivo.
Acute Disease↗
Development of dysmyelopoietic syndrome in a hairy cell leukemia patient treated with chlorambucil: cytogenetic and morphologic evaluation.
A splenectomized patient with hairy cell leukemia (HCL) who had received chemotherapy with a low-dose alkylating agent for 2 years developed dysmyelopoietic syndrome (DMPS), the first such case to be described. A portion of his marrow remained chronically involved with HCL, but the remainder evolved from being morphologically and karyotypically normal to involvement with DMPS, with cells having a bizarre karyotype. Three of four metaphase cells had consistent abnormalities, with a missing chromosome No. 5, structural rearrangements resulting in deletion of part of the long arm of chromosome No. 7, deletion of 2q, and a small ring chromosome; upon further clonal evolution, a translocation between chromosomes No. 12 and 15 and deletion of the long arm of chromosome No. 19 were seen. We therefore add HCL patients to the growing list of those at risk of developing a secondary hematologic malignant disease possibly due to cytotoxic therapy for their primary disorder.
Bone Marrow↗
The predictive value of initial cytogenetic studies in 148 adults with acute nonlymphocytic leukemia: a 12-year study (1970-1982).
When leukemic blood or marrow specimens from 148 adults with newly diagnosed acute nonlymphocytic leukemia (ANLL) were studied with chromosome banding techniques, 79 were found to have clonal abnormalities. Among 130 treated patients, the 53 with initially normal karyotypes had a significantly longer survival rate than the 16 in whom no normal metaphases were observed (p = 0.02). The 55 patients with both normal and abnormal metaphase cells had an intermediate survival. Once a complete remission had been attained, however, there was no significant difference in median survival between those patients with entirely normal karyotypes and those with abnormal karyotypes. Among the various FAB morphologic subsets of ANLL, the differences in complete remission rate and overall survival between the various cytogenetic subsets were greatest in acute myelogenous leukemia (AML, M1 + M2). The presence of an abnormal clone was a more important predictor of clinical outcome (p = 0.02) than the presence of normal stem cell clones. Aneuploidy alone (hyperdiploidy or hypodiploidy) was not of predictive value, indicating that the use of banding techniques to identify structural rearrangements in pseudodiploid cells was essential. Clonal chromosomal abnormalities were nonrandom and acquired, and specific abnormalities were closely associated with specific clinical-pathologic subsets of ANLL. All 13 patients with acute promyelocytic leukemia and adequate cytogenetic specimens had t(15;17); this translocation was not found in any other subset of ANLL. Six patients with AML (M2) had t(8;21) or a variant of this rearrangement. Seven patients had inv(16)(p13q22) associated with acute myelomonocytic leukemia (AMMoL, M4) and abnormal marrow eosinophils. Two patients had ins(3;3) and thrombocytosis. Four patients had a translocation involving 11q, but none of these had acute monocytic leukemia (AMoL, M5); no patient had del(11q).
Acute Disease↗
Further chromosome studies on Wilms' tumor cells of patients without aniridia.
We studied chromosomes in Wilms' tumor cells of two patients without aniridia who had a normal constitutional karyotype. In both tumors, trisomy for 1q occurred as the result of a t(1;16), although the breakpoints in each chromosome differed in the two tumors. No 11p rearrangements could be detected, whereas in our previous patient an interstitial deletion of 11p13 was present in all tumor cells. Thus, trisomy for 1q may be another pathway leading to the development of Wilms' tumor, although the effect of the deletion of 16q cannot be assessed at present.
Child, Preschool↗
Consistent chromosome abnormalities in human leukemia and lymphoma.
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Chromosome Aberrations↗
An improved technique for sequential R-, Q- and C-banding of bone marrow chromosomes.
A procedure for the sequential staining of metaphase cells to provide R-banding, Q-banding and C-banding of chromosomes is described. The combined techniques allow more precise identification of marker chromosomes and more accurate definition of breakpoints in the consistent chromosome translocations that are associated with certain human malignancies.
Barium↗
Lymphoblastic lymphoma: cytogenetic, pathologic, and immunologic studies.
Cytogenetic, pathologic, and immunologic studies were done on 10 patients with lymphoblastic lymphoma (LL). The median age was 21 years, and males predominated in a ratio of 9:1. At the time of diagnosis, 6 of the 10 patients had an anterior mediastinal mass, 3 had bone marrow involvement, and 2 had central nervous system involvement. All patients were treated with intensive combination chemotherapy. The median survival of the 8 patients who died (7 of whom were adults) was 10.5 months; all 8 achieved only a partial remission. Two other patients were children; they continue in complete remission. Immunologic marker studies were done on 9 of the patients; 5 had T-cell LL, and the other 4 had non-T, non-B LL. In a study of T-cell subpopulations with the use of monoclonal antibodies, the malignant T cells of the 2 patients tested appeared to be mature thymocytes. Clonal chromosome abnormalities were seen in involved tissues from 8 patients; the other 2 patients had a normal karyotype. A 9q+ chromosome, a 6q- chromosome, and a 1q-chromosome associated with 1q trisomy were each seen in 2 patients. No patients had a 14q+ chromosome, which is the most common abnormality in various lymphoproliferative disorders, including other T-cell malignant diseases. The variable chromosome pattern in LL could be related to the heterogeneity of the immunologic phenotype of the malignant T cells. More data are needed before it can be established whether there are any correlations between a particular karyotype and the immunologic phenotype of LL cells.
Adolescent↗
Cancer advisory board.
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Governing Board↗
Response to 5-azacytidine in patients with refractory acute nonlymphocytic leukemia and association with chromosome findings.
Fifteen patients with acute nonlymphocytic leukemia (ANLL) who either had a relapse after a previous complete remission (nine patients) or progressive disease after initial induction attempts with combination chemotherapy (six patients) were treated with 5-azacytidine. Five patients (33%) achieved a complete remission (CR); of these, three had a relapse and died 30, 35, and 38 weeks after 5-azacytidine therapy was begun. Two patients are still alive at 39 and 138 weeks. Chromosomes were analyzed at the time of diagnosis; ten patients had a normal karyotype and five had an abnormal karyotype. Three of the five CR patients had an abnormal karyotype initially. Two of these individuals had a translocation of chromosomal material from a No. 8 chromosome to a No. 21 chromosome, t(8;21); this particular translocation has been associated with a better prognosis than have other types of chromosomal abnormalities in patients with ANLL. Even when abnormal chromosomes are present, 5-azacytidine can induce complete remission in patients with previously treated ANLL.
Adult↗
Identification of the constant chromosome regions involved in human hematologic malignant disease.
Specific consistent chromosome translocations are regularly observed in certain human leukemias and lymphomas. For the myeloid leukemias, the constant recombinants are: the long arm of 9 to chromosome 22 in chronic myeloid leukemia, the long arm of 21 to chromosome 8 in acute myeloblastic leukemia, and the long arm of 17 to chromosome 15 in acute promyelocytic leukemia. Three related translocations are seen in Burkitt lymphoma and B cell acute lymphocytic leukemia; in each one, chromosome 8 is involved with chromosome 2, 14, or 22. Analysis of a complex translocation affecting chromosomes 8 and 14 indicates that the translocation of chromosome 8 to chromosome 14 is the critical constant rearrangement. The analysis of the DNA at the translocation sites of these chromosomes, rather than the reciprocal of each translocation, appears to be the most productive focus for initial study. The various immunoglobulin loci are located in chromosomes 2, 14, and 22, the chromosomes regularly involved in translocations in Burkitt lymphoma and B cell acute lymphocytic leukemia.
Chromosome Aberrations↗
Establishment, characterization and differentiation induction of a new human diploid myelomonocytic cell line (HL-92) derived from a patient with acute myelomonocytic leukemia.
With very few exceptions, it has not been possible to grow human myeloid cells for long periods in culture. We have recently developed techniques enabling the long-term in vitro propagation of normal immature myeloid cells from fresh foetal cord blood and monocytes from normal adult peripheral blood, and have utilized these procedures to initiate cultures of fresh peripheral blood leukocytes from leukemic donors. In four of 26 leukemic samples tested, leukocyte replication beyond that obtained in control cultures was observed, and in one of these HL-92, derived from the peripheral blood of a patient with acute myelomonocytic leukemia, the culture has continued to replicate slowly for over 2 years under the special growth conditions. Morphological, cytochemical, immunological and functional studies show that the culture consists predominantly of immature myeloid cells (myeloblasts through to myelocytes) but also contains some mature neutrophils and monocytes. At least a portion of HL-92 cells express Fc and complement receptors, contain histacompatibility locus antigens, including HLA-DR, and release GM-CSA, low levels of PGE and lysozyme. HL-92 cells can be induced with DMSO or RA to differentiate into mature neutrophils (an increase from 20 to 70% of the cell population) as determined by morphology, by an increase in phagocytic cells, and superoxide anion production. Fresh leukocytes from the patient's bone marrow appeared to have a diploid karyotype. However a consistent chromosomal abnormality observed in HL-92 was a deletion in the long arm of chromosome 11 [del(11)(q23)]. This is consistent with recent observations in monocytic leukemia. Since the few other established human myeloid cell lines have various chromosomal abnormalities, and some respond to differentiation inducers, while others do not, there appears to be no detectable common chromosome change required either for in vitro growth of myeloid cells or their response to inducers of differentiation. These cell lines and the application of the techniques described here for the growth of myeloid cells from other leukemic or normal sources should be helpful in the study of normal and leukemic myeloid cell growth and differentiation.
Cell Line↗
Chromosome abnormalities in malignant hematologic diseases.
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Adult↗
Nonrandom chromosome abnormalities in angioimmunoblastic lymphadenopathy.
Cytogenetic and pathologic studies were performed on six patients with angioimmunoblastic lymphadenopathy (AILD). All six had diffuse lymphadenopathy; five had fever, four had weight loss, and four had a diffuse erythematous rash. All patients except one had a polyclonal elevation of immunoglobulin. All patients had diagnostic findings in lymph node (LN) and bone marrow (BM) biopsies. Two patients died of progressive AILD; one patient died after transformation of AILC to immunoblastic sarcoma (IBS); one patient died of gastrointestinal bleeding of unknown cause. The remaining two patients, who have achieved complete remission with intensive chemotherapy, are alive 20 and 8 mo after the diagnosis; one of these had AILD and the other, both AILD and IBS. Despite diagnostic BM biopsy findings, none of the patients had chromosome abnormalities in their BM cells. In studying LN cels of 5 patients, however, we found chromosome abnormalities in each; clonal abnormalities were detected in two, both clonal and nonclonal abnormalities in two, and only nonclonal single-cell abnormalities in one. An extra chromosome 3, seen in four patients, was clonal in two and nonclonal in the two others. Cells with +5, +15, +19, +21, +22 were seen in two patients. All patients had 50% or more normal dividing cells in their LN. The mosaicism of unrelated abnormal cells in their LN. The mosaicism of unrelated abnormal karyotypes that was seen in four patients suggests that this malignant tumor is not necessarily monoclonal in its early stages, but that one clone may be selected and predominate in the late stage. Because nonrandom acquired clonal chromosome abnormalities are a consistent feature of malignancies, our data suggest that AILD may be a malignant disease despite its original description as a benign proliferative process. Therefore, it may require aggressive chemotherapy.
Aged↗