Chromosomal localization of the human T cell receptor beta-chain genes.
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Chromosome Mapping↗
Biomedical subjects
J D Rowley
Publications and source records attributed to J D Rowley.
Trisomy 8 in human hematologic neoplasia and the c-myc and c-mos oncogenes.
The c-mos and c-myc proto-oncogenes have been assigned to bands q22 and q24, respectively, of human chromosome No. 8. A gain of chromosome No. 8 is the most common abnormality observed in myeloproliferative diseases. By using probes specific for the c-mos and c-myc genes, we have analysed the genomic DNA from peripheral blood and bone marrow samples from 15 patients with various malignant myeloid diseases, including leukemia and myelodysplasia, and from one patient with non-Hodgkin's lymphoma, all of whom have trisomy for chromosome No. 8. Except for one patient, the c-mos and c-myc genes were found in restriction fragments of germline size. In one patient with myelodysplasia, one c-myc allele was rearranged in a Hind III fragment, the other allele being normal. Thus, trisomy 8 associated with human hematologic neoplasia is generally not related to gross rearrangements of the c-mos or c-myc genes.
Anemia, Refractory↗
Insertion (10;11)(p11;q23q24) in two cases of acute monocytic leukemia.
An insertion (10;11)(p11;q23q24) was found in bone marrow metaphase cells from two children with acute monocytic leukemia (AMoL-M5b). This rearrangement involves a small chromosomal segment of 11q and may be misinterpreted as a deletion of 11q. Insertion (10;11) may represent a new recurring abnormality involving 11q associated with acute leukemia of the M5b type.
Adolescent↗
c-src is consistently conserved in the chromosomal deletion (20q) observed in myeloid disorders.
The proto-oncogene c-src has been mapped to two bands in human chromosomes, 1p36 and 20q13, both of which are involved in rearrangements in human tumors. In particular, deletions (loss of part of a chromosome) of the long arm of chromosome 20, del(20q), are commonly observed in hematologic malignant diseases. By using in situ chromosomal hybridization of a c-src probe to metaphase cells prepared from leukemic bone marrow cells of three patients with a del(20q), we observed specific labeling on the deleted chromosome in each patient, indicating that the c-src locus was conserved. The presence on the rearranged chromosomes of c-src, which is normally located on the most distal band of 20q, indicated that the deletions were not terminal as they appeared to be on the basis of chromosome morphology, but rather that they were interstitial. The location of c-src relative to the distal breakpoint in these deletions is unknown. By using the v-src probe in Southern blot analysis of genomic DNA from three patients with a del(20q), we found that no major genomic rearrangements or amplification of the c-src genes had occurred within the regions homologous to v-src. Our observation that c-src is consistently preserved in these rearranged chromosomes suggests that this gene may play a role in the pathogenesis of some myeloid disorders.
Aged↗
Isolation and analysis of the 21q+ chromosome in the acute myelogenous leukemia 8;21 translocation: evidence that c-mos is not translocated.
Acute myelogenous leukemia (AML), subgroup M2, is associated with a nonrandom chromosomal translocation, t(8;21)(q22,q22). The oncogene c-mos also has been localized to the q22 band on chromosome 8. There is also evidence that genes on chromosome 21 may be important in the development of leukemia. To determine whether the c-mos oncogene has been translocated in AML-M2 with this translocation and to isolate DNA sequences and genes from these two chromosomes that may be important in malignancy, we constructed somatic cell hybrids between a Chinese hamster ovary cell (CHO) mutant defective in glycine metabolism and myeloblasts with an 8;21 translocation from a patient with AML. We isolated the 21q+ chromosome of this translocation in a somatic cell hybrid and showed that the c-mos oncogene had not been translocated to chromosome 21, ruling out the possibility that translocation of c-mos to chromosome 21 is necessary for development of AML-M2. In addition, there was no detectable rearrangement of the c-mos locus within a 12.4-kilobase region surrounding the gene, indicating that rearrangement of the coding region of the gene itself or alteration of proximal 5' or 3' flanking sequences is not involved. We used this hybrid to determine whether specific DNA sequences and biochemical markers from chromosomes 8 and 21 had been translocated in this case.
Animals↗
Chromosomal localization and characterization of c-abl in the t(6;9) of acute nonlymphocytic leukemia.
Acute nonlymphocytic leukemia associated with the chromosomal translocation t(6;9)(p23;q34) is an entity that is frequently associated with basophilia, which it shares with chronic myelogenous leukemia. The breakpoint on chromosome 9, q34, appears to be cytogenetically identical in both malignancies and is the site of the cellular oncogene c-abl. We investigated the role of c-abl in cells from two patients with the t(6;9) using in situ chromosomal hybridization, Southern hybridization, and in vitro phosphorylation. We showed that c-abl is not translocated from chromosome 9, resulting in a breakpoint that is on the 3' side of this gene. The t(6;9) translocation does not appear to result in the production of an aberrantly sized protein product or in the acquisition of in vitro tyrosine kinase activity. This is in direct contrast to the findings in chronic myelogenous leukemia, in which c-abl is translocated, leading to the production of a structurally altered c-abl protein with activated tyrosine kinase. Lastly, we demonstrated that the cells of one patient contain sequences from chromosome 9 inserted at the junction of a reciprocal translocation between chromosomes 4 and 10 on the 4q+ chromosome. This insertion, which is at least 100 kilobase pairs in length, represents a duplication and translocation of the protein coding region of c-abl.
Adult↗
Philadelphia chromosome-negative chronic myelogenous leukaemia: a morphological reassessment.
Morphological re-examination of 25 cases classified as Ph1-negative chronic myelogenous leukaemia (CML), with particular attention to the recent French-American-British (FAB) group proposals for the diagnosis of the myelodysplastic syndromes, led to reclassification of all but one of these cases. Upon review of pretreatment material, seven of the 25 cases (28%) were considered to represent myeloproliferative and reactive conditions other than CML. Of the remaining 18 cases, 17 (94%) were reclassified as myelodysplastic syndromes (MDS). These included one case of refractory anaemia (RA), three of refractory anaemia with excess of blasts (RAEB), four of RAEB in transformation (RAEBT), and nine of chronic myelomonocytic leukaemia (CMMoL). Haematological findings in these 17 patients were compared to those in 50 randomly selected patients with Ph1-positive CML. Whereas an absolute basophilia in the peripheral blood was a nearly constant feature in the Ph1-positive group, it was lacking in all but one of the patients with myelodysplastic syndromes. Differences in the pattern and degree of dysplasia were also noted. Only one of the 25 cases studied was considered morphologically and clinically indistinguishable from Ph1-positive CML. It appears that Ph1-negative CML constitutes a heterogeneous group of prognostically distinct disorders and that, in most instances, careful morphologic examination will permit precise classification.
Anemia, Aplastic↗
Localization of the oncogene c-erbA1 immediately proximal to the acute promyelocytic leukaemia breakpoint on chromosome 17.
Using in situ hybridization, c-erbA1 has been mapped immediately distal to the translocation breakpoint on chromosome 17 in fibroblasts with a karyotype 46,XX, t(15;17)(q22;q11). Previous work has shown that c-erbA1 is proximal to the translocation breakpoint on chromosome 17 in the t(15;17)(q22;q12-21) in acute promyelocytic leukaemia. The oncogene can therefore be localized to the region of chromosome 17 between the breakpoints in 17q11 and 17q12-21.
Chromosome Banding↗
The relation of oncogenesis and cytogenetics in leukemia and lymphoma.
Recent advances in both molecular biology and cancer cytogenetics have provided valuable tools for the study of human oncogenesis. Cellular homologues of viral transforming genes (oncogenes) have been mapped to precise sites on human chromosomes, many of which are involved in specific chromosome translocations in human malignant diseases. Moreover, specific chromosome abnormalities, such as the Ph1 chromosome, have diagnostic implications. Sufficient data are now available for both acute myeloid and lymphoid leukemia so that the patient's response to therapy and survival can be correlated with the karyotype; it was also shown that the karyotype of the leukemic cells provides significant independent prognostic information. This review summarizes the specific translocations of human leukemias and lymphomas, their clinical implications, and the cellular oncogenes associated with them. Possible mechanisms of oncogenesis and future areas of investigation are also discussed.
Burkitt Lymphoma↗
Report of Children's Cancer Study Group.
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Acute Disease↗
Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia.
Fourteen patients with acute nonlymphocytic leukemia (ANLL) or dysmyelopoietic syndromes were found to have abnormalities involving the long arm of chromosome 3. In eight patients, the structural rearrangements involved both bands 3q21 and 3q26 and included t(3;3) (four patients), inv(3) (three patients), and ins(5;3) (one patient). Before treatment, seven of these eight patients had platelet counts above 100,000 per microliter, five had normal or elevated platelet counts, and four had significantly elevated platelet counts (600,000 to 1,731,000 per microliter). In each of the eight cases, normal or elevated platelet counts were associated with marked abnormalities of megakaryocytopoiesis, including increased numbers of megakaryocytes and numerous micromegakaryocytes. Classification within the French-American-British system was difficult in most of these cases; however, the leukemia in five of the eight patients with abnormalities of chromosome 3 that involved both bands 3q21 and 3q26 was classified as M4. The remaining six of the 14 patients had translocations between chromosome 3 and another chromosome. None involved both bands 3q21 and 3q26, and a break in either q21 or q26 was noted in only two patients. One of the six, who had ANLL (M4) with a normal platelet count, had a 3;5 translocation which involved band 3q25. These data suggest that in patients with ANLL, abnormalities of chromosome 3 which simultaneously involve bands 3q21 and 3q26 are associated with unusually high platelet counts.
Adult↗
Chromosome abnormalities in human leukemia as indicators of mutagenic exposure.
It is from an analysis of these data that I proposed that losses of all or part of the long arm of chromosomes 5 and/or 7 may be indicators of exposure to mutagenic agents (8). Moreover, our analysis of the regions of chromosomes 5 and 7 that are consistently missing can define the critical region of each chromosome with some precision. Looked at from another perspective, the frequency of losses of chromosomes 5 and/or 7 may be an indicator of the proportion of ANLL in each particular population that is related to some mutagenic exposure. These aberrations are most frequent in cells of patients who were previously exposed to various cytotoxic regimens for treatment of a primary (usually malignant) disease; these patients are considered to have 2 degrees ANLL. Among patients with ANLL de novo, abnormalities of chromosomes 5 and 7 are much more frequent in older than younger patients. Finally, among adult patients with ANLL de novo, -5 and -7 are more common in those whose occupations could potentially expose them to mutagenic agents such as chemicals, pesticides, or petroleum products. With regard to chromosome 5, most of these deletions are interstitial and always include 5q23 through q31, which I have called the critical region. Although I am less certain with regard to chromosome 7, it appears that the critical region that is consistently deleted may be 7q32 or 7q34-35.
Adult↗
Hypercalcemia and lytic bone lesions in a patient with B-cell non-Hodgkin's lymphoma.
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Adult↗
Cancer advisory board.
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National Institutes of Health (U.S.)↗
Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia.
Cytogenetic specimens were obtained from blood or bone marrow in 27 patients with acute promyelocytic leukemia, including four with the microgranular variant. A 15;17 translocation was identified in 21 to 100 percent of metaphase cells from all 27 patients. The structural rearrangement was identical in every case, and the breakpoints were assigned to 15q22 and 17q21.1. Twelve patients had complete remission, and two (both with the microgranular variant) have had unmaintained continuous remission longer than four years. These data indicate that the 15;17 translocation may be found in every patient with acute promyelocytic leukemia if optimal chromosome analysis is performed.
Adolescent↗
Fourth International Workshop on Chromosomes in Leukemia 1982: Chromosomes in acute promyelocytic leukemia.
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Adolescent↗
A morphologic and cytochemical study of acute myelomonocytic leukemia with abnormal marrow eosinophils associated with inv(16)(p13q22).
Nineteen patients with acute nonlymphocytic leukemia were found to have a pericentric inversion of chromosome 16. All were classified as having acute myelomonocytic leukemia (M4) according to French-American-British Cooperative Group (FAB) criteria. Consistent abnormalities of marrow eosinophils were present. In 15 of the 19 patients, the number of eosinophils was increased. Morphologic abnormalities of eosinophils were present in all patients, the most striking being the presence of large basophilic staining granules in 18 of the 19 patients. In most cases we also found a population of cells with morphologic features of both eosinophils and monocytes. Eosinophils showed atypical cytochemical reactions with PAS in ten of ten cases studied, with naphthol ASD Chloroacetate in ten of ten cases, and with combined naphthol ASD Chloroacetate esterase- chlorazol fast pink in seven of nine cases tested. The presence of inv(16) defines a distinct subset of ANLL with consistent morphologic and cytochemical features.
Adolescent↗
Chromosome abnormalities in tumor cells from patients with sporadic Wilms' tumor.
The karyotype of nine of 11 Wilms' tumors was successfully analyzed using chromosome banding techniques. Peripheral lymphocytes had a normal karyotype in all six analyzed cases. Cultured cells from one tumor had a normal karyotype; however, they appeared to be fibroblasts. A chromosome 11 deletion, del(11)(p13p14), similar to that seen in patients with sporadic aniridia, was found as the sole abnormality in cells from one tumor. Abnormalities of chromosome 1 resulting in trisomy for the long arm (q21-q31) were found in five cases. Two of them had a translocation involving 1q and 16q, although the breakpoints in each chromosome appeared to differ in the two cases. Two patients had an isochromosome of the long arm, i(1q), and a fifth case had a duplication of the long arm as a result of karyotypic evolution. Chromosome 16 abnormalities were found in three cases, resulting in the partial monosomy of the long arm, sharing q22 as a common deletion. The same three cases also had trisomy 1q due to an unbalanced translocation of 1q or an i(1q). Trisomy for both chromosomes 9 and 12 were present in three cases. Two patients each had whole or partial trisomy of chromosomes 6, 7, 8, 17, and 18. Our data show that although an 11p deletion can occur as a mutation confined to tumor cells, the most common changes are trisomy for 1q, and less often a deletion of 16q.
Adolescent↗