B cell acute lymphoblastic leukemia (ALL) with a 14q+ chromosome abnormality.
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An adult patient with acute lymphoblastic leukemia associated with a 14q+ marker chromosome is presented. The abnormality resulted from a translocation of material from the long arm of chromosome 11. The leukemic cells were found to be B cells on the basis of surface immunoglobulins, lack of receptors for sheep erythrocytes, and a characteristically low level of adenosine deaminase activity. In other patients with ALL studied by us or reported by others in whom chromosome banding was done, a 14q+ chromosome was present in only one instance, also a case of B cell ALL. These two cases are the only examples of B cell ALL studied with chromosome banding reported to date. The frequent occurrence of a 14q+ chromosome in other malignant lymphoproliferative diseases of B cell origin suggests that a general association may exist between the 14q+ abnormality and B cell neoplasms. Cytogenetic analysis may therefore be useful in defining subtypes of ALL and in relating specific chromosomal abnormalities to lymphoproliferative disorders. (+info)
Four families with immunodeficiency and chromosome abnormalities.
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Six children, with severe deficiency of some or all of the immunoglobulins and minor somatic abnormalities, had chromosomal abnormalities: (1) 45,XY,t(13q/18q), (2) 46,XY,21ps +, (3) two brothers 46,XY (inv. 7) (4) 45,X,t(11p/10p)/46X,iXq,t(11p/10p) and, (5) in addendum, 45,XX,-18;46,XX, r18. The chromosome abnormalities were detected in B- as well as T-lymphocytes (as evidenced by using both PHA- and PWM-stimulated cultures) in all probands, but one was mosaic in PHA culture, although all his PWM-stimulated cells were abnormal. Chromosomal variants were also detected in relatives of three and immunodeficiency in relatives of two. (+info)
Association of the translocation (15;17) with malignant proliferation of promyelocytes in acute leukemia and chronic myelogenous leukemia at blastic crisis.
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Cytogenetic studies were performed on nine patients with acute promyelocytic leukemia. Every patient had an identical translocation (15;17) or, in one case, a variant three-way rearrangement between chromosomes 7, 15, and 17. Another patient with chronic myelogenous leukemia was examined at the time of blastic crisis when the patient's bone marrow was infiltrated by hypergranular promyelocytes and blasts. Bone marrow cells contained a t(15;17) as well as a Ph1 chromosome. Only the latter abnormality was observed in the chronic phase of the disease. The translocation (15;17) was detected in all ten patients when bone marrow or peripheral blood cells were cultured for 24 hours prior to making chromosome preparations. However, the t(15;17) was not seen in three of these same cases when bone marrow cells were processed directly. These findings indicate that the t(15;17) is closely associated with acute proliferation of leukemic promyelocytes and that detection of this karyotypic defect may be influenced by the particular cytogenetic processing method used in different laboratories. An analysis of the banding pattern in the variant translocation provided additional evidence favoring chromosomal breakpoints at or very near the junction between bands 17q12 and 17q21 and at 15q22. (+info)
Somatic shift to homozygosity for a chromosomal polymorphism in a child with acute lymphoblastic leukemia.
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A 12-year-old girl with acute lymphoblastic leukemia (ALL) had two types of acquired cytogenetic abnormalities in her pretreatment peripheral blood and bone marrow: hyperdiploidy due to tetrasomy 8, 10, and 21; and, in the hyperdiploid cells, a shift from heterozygosity to homozygosity for a polymorphic variant on chromosome 15. Both abnormalities disappeared after chemotherapy, when the patient entered clinical remission. It has recently been found that shifts to homozygosity occur in retinoblastoma and Wilms' tumor. Our observation extends this finding to leukemia and indicates that such shifts may have general importance in tumorigenesis. (+info)
Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia.
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The importance of banded chromosome analyses in predicting long-term outcome in acute lymphoblastic leukemia (ALL) was evaluated in this follow-up study of 329 patients from the Third International Workshop on Chromosomes in Leukemia. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, translocations involving 8q24,t(4;11), 14q+, 6q-] or, in the remaining cases, modal number [less than 46, 46, 47 to 50, greater than 50]. Achievement and duration of complete remission (CR) and survival differed among chromosome groups (P less than .0001). Karyotype was an independent prognostic factor for duration of first CR and survival, even when age, initial leukocyte count (WBC), French-American-British (FAB) type, and immunologic phenotype were considered. Among adults, prolonged remission and survival were uncommon in all chromosome groups. Only in the normal karyotype group was median survival even two years. Among children, striking differences in long-term remission and survival were seen depending upon karyotype. Children in the greater than 50 group did best, with 70% remaining in first CR for a median duration in excess of five years. Children in the 47-50, 6q-, and normal karyotype groups also had prolonged survivals. In contrast, certain translocations [t(9;22)(q34;q11), t(4;11)(q21;q14-23), t(8;14)(q24;q32)] identified children who had short survivals, even in the presence of favorable prognostic factors including a low WBC, L1 morphology, and non-T, non-B immunologic phenotype. We conclude that chromosome analysis is required at diagnosis in patients with ALL, and that children with these specific translocations should be managed as having high-risk ALL. (+info)
Isolation of cDNA clones coding for the alpha and beta chains of human propionyl-CoA carboxylase: chromosomal assignments and DNA polymorphisms associated with PCCA and PCCB genes.
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Propionyl-CoA carboxylase [PCC, propanoyl-CoA:carbon-dioxide ligase (ADP-forming), EC 6.4.1.3] is a biotin-dependent enzyme involved in the degradation of branched-chain amino acids, fatty acids with odd-numbered chain lengths, and other metabolites. Inherited deficiency of the enzyme results in propionic acidemia, an autosomal recessive disorder showing considerable clinical heterogeneity. To facilitate investigations of enzyme structure and the nature of mutation in propionic acidemia, we have isolated cDNA clones coding for the alpha and beta polypeptides of human PCC. Sequences of two peptides derived from human liver PCC were used to specify oligonucleotide probes that were then used to screen a human fibroblast cDNA library. Two classes of cDNA clones were thus identified. One class contained the anticipated Ala-Met-Lys-Met sequence, corresponding to the biotin binding site found in several biotin-dependent carboxylases, thus confirming the alpha-chain assignment of these clones. In addition, they contained the deduced amino acid sequence of two of the sequenced peptides, including that of one of the oligonucleotide probes. The second class, coding for the beta polypeptide, contained the sequences of four peptides, including the sequence corresponding to the other oligonucleotide probe. Blot hybridization of RNA from normal human fibroblasts revealed a single mRNA species of 2.9 kilobases coding for the alpha polypeptide and two species of 4.5 and 2.0 kilobases detected for the beta polypeptide. By use of a panel of somatic mouse-human hybrids, the human gene encoding the alpha polypeptide (PCCA) was localized to chromosome 13, while the gene encoding the beta polypeptide (PCCB) was assigned to chromosome 3. Restriction fragment length polymorphisms were identified, at both PCCA and PCCB, that should prove useful to individual families at risk for propionic acidemia. (+info)
Molecular cloning of the human esterase D gene, a genetic marker of retinoblastoma.
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Retinoblastoma, the most common intraocular tumor, represents one of the prototypes of inheritable cancers. To elucidate the mechanisms that give rise to this tumor, the retinoblastoma gene (RB) must be molecularly cloned. The difficulty encountered in cloning the gene is that little of its function or structure is known. The human esterase D gene, on the other hand, has been localized cytogenetically to the same sub-band of chromosome 13q14:11 as the RB gene. The esterase D gene thus provides a convenient starting point for cloning the RB gene. In this communication, we describe the isolation of the esterase D cDNA clone. Its identification is based on three lines of evidence. This cDNA encodes a protein immunologically related to the esterase D protein. The deduced amino acid sequences of this clone contain sequences identical to the three CNBr-cleaved peptides of the esterase D protein. This clone is mapped to the chromosome 13q14 region by Southern genomic blotting using different deletion mutants. The availability of this clone should allow for the cloning of the RB gene by chromosome walking; the diagnosis of genetic defects such as retinoblastomas and Wilson disease, whose genes are closely linked to the esterase D gene; and the exploration of the large family of human esterase genes. (+info)
Cloning of the esterase D gene: a polymorphic gene probe closely linked to the retinoblastoma locus on chromosome 13.
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The study of recessive oncogenes such as those responsible for retinoblastoma and Wilms tumor is difficult because the gene products involved are unknown and because the diseases are not associated with unique cellular or molecular phenotypes suitable for genetic manipulation. Since the gene for esterase D (ESD) is known to be tightly linked to the retinoblastoma locus (RB1) in the q14.1 band of chromosome 13, we have cloned the ESD gene from a human cDNA library by using oligonucleotides specific for a partial amino acid sequence of the purified enzyme to provide a genetic marker for further studies on retinoblastoma. The putative ESD gene codes for a message of 1.2 kilobases, which is present in all cell types examined, and maps to 13q14.1, thus confirming that it is the ESD gene. Restriction enzyme analysis reveals a restriction fragment length polymorphism with Apa I; this polymorphism results from the heterozygosity of 32% of the individuals tested and is shown to be useful in identifying carriers of the mutation responsible for retinoblastoma. A preliminary screen of 24 retinoblastoma tumors by Southern blot did not reveal any homologous deletions or rearrangements of the ESD locus. (+info)