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PubMed1990

[Role of hemopoietic stem cells and progenitor cells in preleukemia].

Cases of myelodysplastic syndrome (MDS) that have evolved into overt leukemia may be retrospectively termed preleukemia. Studies with X-chromosomal markers in females strongly suggest that preleukemia originates from transformation of a very early hemopoietic stem cell. Growth characteristics of myeloblasts in preleukemia indicate that some of the cases already represent early stages of acute leukemia. In other preleukemias clonal evolution towards overt leukemia can be observed. This apparently involves neoplastic transformation of a granulocytic determined progenitor cell.

Colony-Forming Units Assay↗
PubMed1991

The malignant primate?

Speciation and carcinogenesis result from genomic instability at the gametic or at the somatic levels. After an infinity of trials they occur, by chromosome rearrangements, in single individuals or in single cells and evolve by similar chromosomal or clonal evolutions. Loss of heterozygosity for the first event is essential in both processes: in evolution, a chromosomal rearrangement, a pericentric inversion or a Robertsonian fusion, must become homozygous to ensure a reproductive barrier for a new species; Knudson's two-event sequence is a similar situation in cancer. Position effect is equally important: we have shown overexpression of the SOD1 gene in the orangutan phylum probably by an intrachromosomal rearrangement; the t(9;22) in CML acts by typical position effect. Parental imprinting underlies the evolution of genome function and the unset of certain cancers. Evolution and malignancy are interweaved by viruses and oncogenes since the dawn of life. Cancer uses its intelligence to expand and to destroy the other tissues, using subtle metabolic pathways and a variety of tricks to metastasize other cells. It always wins but saws the branch on which it sits. Mankind also grows exponentially, killing thousands of other species, poisoning the oceans and soft waters, polluting the atmosphere, all for his egoistic needs. Man also travels and metastasizes other Earths. He modifies his genome or that of other species, and develops new technologies for his reproduction. He can destroy the planet in an eyeblink. To be or not to be the malignant primate, that will be the dilemma for the 21st Century.

Animals↗
PubMed1991

Detection of T-cell receptor gamma chain V gene rearrangements using the polymerase chain reaction: application to the study of clonal disease cells in acute lymphoblastic leukemia.

This report describes the development and characterization of a method for the amplification of rearranged V-J segments of the human T-cell receptor gamma chain (TCRG) locus using an adaptation of the polymerase chain reaction (PCR) technique. The technique uses a single pair of 'consensus' primers to amplify rearrangements involving the V gamma I subgroup genes, which are common in malignant cells from acute lymphoblastic leukemia (ALL) patients. Using this method we were able to detect rearrangements in the TCRG locus in disease cells from patients with T-cell ALL (12 of 12), common ALL (10 of 14), and Null cell ALL (2 of 2) at presentation. Monoallelic and biallelic rearrangements involving V gamma I subgroup genes were identified by restriction analysis of PCR products from DNA samples from a T-cell leukemic cell line, T-cell clones, and disease cells from patients with ALL of T-and B-cell lineage at presentation. These results confirmed the presence of cell clones within the presentation samples and, in one case, confirmed the persistence of the original malignant cell clone at relapse. This is a rapid and specific method for the detection and characterization of rearrangements of the TCRG locus without recourse to Southern blotting. Therefore, the PCR technique described herein can provide the basis for the study of clonal evolution and minimal residual disease on a high proportion of patients with ALL.

Alleles↗
PubMed1991

Near haploid acute lymphoblastic leukemia: seven new cases and a review of the literature.

Seven new cases are described of near haploid acute lymphoblastic leukemia (ALL) and the findings reviewed together with updated complete remission duration and survival data for the 21 cases already published. The patients were four males and three females, with an age range 2-19 years; all had an immunophenotype consistent with common ALL. The poor prognostic outlook for patients with near haploid ALL is confirmed by the median remission duration of 14 months for these patients, which is comparable to that for the previously published cases. The pattern of chromosome loss was marked particularly by the presence of two copies of chromosomes 10, 14, 18, 21 and both sex chromosomes. Populations of hyperdiploid cells with double the near haploid number were observed in six of the patients, one of whom demonstrated further clonal evolution, and it is proposed that some cases classified as hyperdiploid ALL with greater than 50 chromosomes may also have arisen from a near haploid stem line.

Adolescent↗
PubMed1990

Atrophy, hormones, genes and viruses in aetiology germ cell tumours.

This chapter reviews the evidence that testicular germ cell atrophy could be the final common pathway for all of the established and postulated risk factors for induction of testis tumours. The evidence from age incidence studies shows that the tumour peak incidence follows the curve of sexual activity in the male, and this provides the starting point for the argument that this tumour is dependent on endocrine factors for its induction. The data from epidemiological studies confirming the high frequency of atrophogenic events and occurrence of low sperm counts in more than 75% of patients provide the principal evidence in support of this hypothesis. The need for more information on hormone sensitivity of this group of tumours and in particular the more differentiated variety, ie seminoma, is highlighted. Information on levels of DNA repair enzyme activity as an explanation of radiosensitivity and chemosensitivity of this group of tumours is also needed. The relationship of HLA linked immune response genes to susceptibility to testicular atrophogenic virus infection needs further investigation, particularly in view of the recent introduction of widespread prepubertal vaccination against mumps virus, one of the most clearly identified testicular atrophogenic viruses. The paper concludes with an examination of the influence of carcinogens and radiation and how they relate to modern ideas of clonal evolution of tumours. The conclusion from this review is that testicular germ cell tumours provide an excellent model of the recent postulate of Ames et al, (1990) that for some cancers mitogenesis might precede mutagenesis, in contrast to the classical view produced from animal models that mutagenic induction is followed by mitogenic promotion.

Atrophy↗
PubMed1991

Karyotypic changes associated with loss of prolactin dependency of rat Nb2 node lymphoma cell cultures.

The parent line of cultured "Nb2 node" lymphoma cells is dependent on the hormone prolactin (PRL) for growth and is widely used for the in vitro bioassay of lactogenic hormones. As reported previously, PRL-independent sublines have been developed in vitro from the parental line by lactogen deprivation. The present study describes the G-banded karyotypes of the Noble (Nb) strain of rat (in which the original lymphoma developed), the PRL-dependent cell line (157th generation), and two of its PRL-independent sublines (1220th and 2372nd generations). The karyotype of the Nb rat was determined to be the same as that of Rattus norvegicus. The stemline karyotype of the PRL-dependent cells contains a number of well-defined chromosomal abnormalities. The PRL-independent sublines examined have the same chromosomal abnormalities as the PRL-dependent cells plus a few additional changes indicative of clonal evolution from the PRL-dependent stemline. The development of PRL independence (as seen in the 1220th generation) was associated with only two karyotypic changes, i.e., loss of the Y chromosome and a translocation involving chromosomes 14 and 17. The recently reported mapping of the rat PRL gene and other PRL-related genes to chromosome 17 suggests that rearrangement of chromosome 17 could be involved in the development of the PRL independence. The PRL-dependent and PRL-independent Nb2 cell lines provide a useful system for studying chromosomal and molecular genetic events associated with the malignant progression of polypeptide hormone-dependent cancers.

Aneuploidy↗
PubMed1991

Cytogenetic analysis of 33 basal cell carcinomas.

Cytogenetic analysis of short-term cultures from 33 basal cell carcinomas (BCC), a type of neoplasm for which no previous karyological data exist, revealed clonal chromosome aberrations, all of them different, in 8 tumors. In 2 cases, 2 cytogenetically unrelated clones were detected, suggesting a multicellular origin in at least a subset of BCC. A remarkably high level of nonclonal structural rearrangements, mostly in the form of seemingly balanced translocations, was found in 23 tumors; namely, in 6 of 8 BCC with clonal karyotypic abnormalities and in 17 of 25 without. It is possible that some of these aberrations represent additional neoplastic clones, thus indicating an even higher level of cytogenetic heterogeneity in BCC. We think that the most likely interpretation of the results is that BCC may have a multicellular origin, reflecting field cancerization of the skin. During subsequent tumor development, the selection pressure narrows down the number of clones that infiltrate the surrounding tissue. The finding by karyotypic analysis of some apparently monoclonal, some polyclonal BCC, may reflect that different tumors have been examined at different points in the clonal evolution of the neoplastic cells.

Aged↗
PubMed1991

Oncogene rearrangements in chronic B-cell leukemia.

Forty-four B-chronic lymphocytic leukemias (CLL) were studied by Southern blot analysis using probes for the Ig genes and bcl-1, bcl-2 (major, minor and 5' breakpoint region), bcl-3, c-myc, and retinoblastoma (Rb) loci. Eight cases had three or more rearranged JH bands, indicating oligoclonality, clonal evolution, or chromosomal translocation. One case had a rearrangement of the bcl-1 locus and three of the bcl-2 locus. In the first case, comigration of the rearranged bcl-1 and JH sequences indicated a t(11;14)(q13;q32) translocation, which, in contrast to previously described cases, seems to be completely reciprocal. One case with a bcl-2 rearrangement showed comigration of the bcl-2 major breakpoint region and a rearranged JH band. This indicates a t(14;18) (q32;q21). The two other cases showed rearrangements of the bcl-2 5' breakpoint region without apparent comigration. No rearrangements were detected of c-myc and bcl-3, located at chromosome 19, nor was a deletion of Rb found. All but three cases had CD5 expression. The exceptions included the t(11;14) and the t(14;18) cases. Our results confirm recent data on rearrangements at the 5' site of bcl-2 in CLL. Additionally, they corroborate the presumption that CD5-negative chronic B-cell leukemias should be considered apart from classical CLL.

Antigens, CD↗
PubMed1990

The hematopoietic defect in aplastic anemia assessed by long-term marrow culture.

Thirty-two patients with aplastic anemia (AA) have been studied using the long-term bone marrow culture (LTBMC) system. Of these patients, 26 had been treated with immunosuppressive therapy including antilymphocyte globulin (ALG) with or without androgens or high-dose methyl prednisolone. The remaining six patients either required no treatment or were studied before therapy was begun. Thirty-one of 32 patients (96%) had defective hematopoiesis in LTBMC with little or no evidence for the generation of primitive progenitor cells. The only exception was a patient with spontaneous recovery of aplasia in whom the defect was less marked. Crossover LTBMC experiments were performed in 23 cases by inoculating (1) patient marrow hematopoietic cells that had been depleted of adherent cells onto preformed, irradiated, normal stromas to assess the proliferative capacity of the hematopoietic cells, and (2) normal marrow hematopoietic cells that were depleted of adherent cells onto preformed, irradiated stromas from patients with AA to assess stromal function. Results of these experiments demonstrated a hematopoietic defect in all patients that was independent of the degree of hematologic recovery after ALG therapy. Only one patient had a probable stromal defect and this coexisted with a defect in the regenerative capacity of hematopoietic cells. We conclude that LTBMC is a sensitive method for detecting and defining the hematopoietic failure in AA. We suggest that the defective hematopoiesis present in all patients studied may be important in the pathogenesis of clonal evolution in AA.

Adolescent↗
PubMedDate not supplied

Cytogenetic studies of 11 meningiomas and their clinical significance. II.

Cytogenetic analyses of 11 consecutive cases of meningiomas from 7 female and 4 male patients are reported. Chromosomal abnormalities were found in all cases. Only two of the cases showed cells with normal karyotype in addition to the abnormal stemline. Two of the cases displayed a more aggressive growth pattern than is usually seen in meningiomas. The first case was characterized by tumor invasion into the bone, a stemline with monosomy 22 and a hyperhaploid sideline. The second case was characterized by recurrency and a hypodiploid stemline. Extended clonal evolution was observed in one case.

Adult↗
PubMed1989

Phenotypic and genotypic heterogeneity in infant acute leukemia. I. Acute lymphoblastic leukemia.

We have studied the immunophenotypic and genotypic features in 35 infants aged less than 1 year with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL). A CD10 (common ALL antigen)-negative, CD19-positive pre-pre-B ALL phenotype was observed in 24 infants. Seventeen of them had blast cells coexpressing myeloid-associated markers such as CD15A (VIM-D5, MZ17) and/or VIM-2, but neither myeloperoxidase nor platelet peroxidase was detected in five of these cases analyzed by electron microscopy. Five patients showed a typical common ALL, five a pre-B ALL phenotype, and one infant was unclassifiable by surface-marker and morphologic analysis. Cytogenetic data, available in 21 of these patients, revealed chromosomal abnormalities involving 11q23 in 10 infants with a CD10-negative pre-pre-B ALL. Immunoglobulin (Ig) and T cell receptor (TCR) gamma, beta and delta gene analysis of 31 infants showed Ig heavy-chain gene rearrangement in all but one patient with evidence for clonal evolution in six and kappa-light-chain rearrangement in three infants. TCR beta-chain and TCR gamma-chain rearrangement occurred in six and five patients respectively, while TCR delta-chain rearrangement was identified in 15 patients. Our data indicate that ALL in infancy may present with heterogeneous immunophenotypic and genotypic features. The high frequency of coexpression of B-lineage and myeloid surface markers as well as of chromosomal rearrangement involving 11q23 suggests that the clonogenic cell of infant ALL may relate to a multipotent progenitor cell in most cases.

Antibodies, Monoclonal↗
PubMed1978

Comparative cytogenetic studies of normal and leukemic lymphoblastoid cell lines during the course of their establishment.

A comparative chromosomal analysis was made of 10 human lymphoblastoid cell lines, four of which originated from normal donor lymphocytes and six of which were from leukemic peripheral blood. For comparison of lymphoblastoid cells with respect to their normal or leukemic origin, cytogenetic studies have been carried out regularly since the beginning of the culture during more than 3 years. Samples were drawn during the three phases previously described for the establishment of these lines. The chromosome distribution remained diploid for at least 2 years in normal cell lines, and the cells were euploid. In contrast, an important variability of the chromosome set was demonstrated during the same period in leukemic cell lines. Moreover, in these lines, it was always possible to observe a nonsystemic pseudodiploidy. After 2 years, a clonal evolution was described in both types of cell lines that carried at least one marker. With a controlled-heating denaturation technique, it was possible to identify the markers as specific to each cell line. The cells with marker chromosomes appeared to have a selective advantage of growth.

Aneuploidy↗
PubMed1989

[A trial for prolongation of chronic phase of chronic myeloid leukemia--maintenance of leukocyte counts within normal range with busulfan].

To prolong the survival of patients with chronic myeloid leukemia (CML), 19 patients were treated with busulfan to keep their leukocyte counts within normal range by controlling bone marrow hyperplasia. The duration of chronic phase in these patients was significantly longer than that in historical controls who were treated conventionally with busulfan. This prolongation was not ascribable to the difference in such prognostic factors between the two therapy groups as splenomegaly, leukocyte count and percentage of peripheral blasts. There was a significant difference again in the duration of chronic phase between the two therapy group even when restricted to each 11 patients with intermediate relative risk (0.7-1.5) according to Sokal et al. Four patients showed thrombocytopenia less than 5 x 10(4)/microliters, but all these patients recovered within 4 months and there was no further critical side effect except subcutaneous bleeding. This study suggests that maintenance of leukocyte count within normal range and suppression of granuloid hyperplasia in bone marrow with busulfan may prolong chronic phase of CML. Probability of clonal evolution may be decreased by reducing the total leukemic cell mass and suppressing cellular turnover of primitive CML stem cells. Another possibility is that prolongation of chronic phase might be dependent on the appearance of normal karyotype clone after long-term bone marrow suppression just like after intensive chemotherapy or alpha-interferon therapy.

Adolescent↗
PubMed1987

Complete or partial homozygosity of chromosome 13 in primary retinoblastoma.

Sixteen retinoblastomas were examined with chromosome 13 polymorphic probes to determine the frequency of homozygosity for the chromosome in the tumors. Each of the tumors had two cytogenetically normal appearing No. 13 chromosomes. Nontumorous cells from the same patients were heterozygous for the various polymorphic chromosome 13 probes used. At least partial homozygosity for a single chromosome 13 was observed in 75% of the tumors. These studies confirm and extend previous studies which suggest that homozygosity or hemizygosity at RBI occurs in the majority of retinoblastomas. We also demonstrate in an additional tumor that rapid clonal evolution from hemizygosity to homozygosity can occur in the tumor.

Cells, Cultured↗
PubMed1986

Biologic and prognostic significance of the presence of more than two mu heavy-chain genes in childhood acute lymphoblastic leukemia of B precursor cell origin.

We examined the arrangement of the mu heavy-chain immunoglobulin (Ig) genes in the leukemic blast cell DNA of 93 children with acute lymphoblastic leukemia (ALL). All cases met morphologic and cytochemical criteria for ALL, lacked detectable T cell surface antigens, and expressed HLA-DR (Ia) antigens. Eighty-three of the 93 patients (89%) were positive for the common acute lymphoblastic leukemia antigen (CALLA), and 20 of 91 (22%) tested had detectable cytoplasmic immunoglobulin. As expected, the heavy-chain lg gene was rearranged in all cases, and the pattern of rearrangements was variable; 23 had one allele rearranged and one in the germ line configuration; 15 had one rearranged and one deleted; and 37 had two rearranged. Unexpectedly, in 18 patients the presence of more than two mu gene-hybridizing bands was detected. Combinations of enzymes and heavy-chain gene probes were used to confirm that the extra bands were not the result of underdigestion of the DNA or DNA restriction site polymorphism. In eight of the 18 patients, we identified an extra chromosome 14 as a possible cause of the extra bands' hybridizing to the mu heavy-chain constant-region probe. In the remaining ten patients, the presence of three or four bands hybridizing with the mu probe suggests the presence of two populations of leukemic cells that may have arisen either by separate leukemic transformation events or by clonal evolution of one clone into two related lines. Although preliminary (2-year follow-up), our data suggest that childhood ALL of B lineage with more than two mu heavy-chain genes, but without extra copies of chromosome 14, may be more resistant to therapy.

Adolescent↗
PubMed1986

Shifts in blast cell phenotype and karyotype at relapse of childhood lymphoblastic leukemia.

Analyses of bone marrow blast cells collected at diagnosis and relapse from 68 children with acute lymphoblastic leukemia (ALL) demonstrated changes in the expression of cell markers in one-fourth of the patients. Loss of the common ALL antigen (CALLA) was a frequent change, occurring in 8 of the 51 cases initially classified as common or pre-B ALL. The HLA-DR antigen was either acquired or lost in 5 of the 68 cases, terminal deoxynucleotidyl transferase was lost in 6 of 25 cases, and reactivity of the T10 antigen with monoclonal antibodies was increased in 6 of 17 cases of non-T cell ALL. Conversion to acute nonlymphoblastic leukemia, so-called lineage switch, was noted in two cases of common ALL and one of pre-B ALL, coinciding with the loss of CALLA. Results of chromosomal analyses in cases with a loss of CALLA implicated several mechanisms in the observed phenotypic changes. In six cases, including each instance of lineage switch, the original karyotype had been replaced by an entirely different abnormal karyotype, suggesting clonal selection or induction of a second malignancy. In another case, the evidence suggested clonal evolution. Our findings demonstrate that sequential phenotypic and cytogenetic studies may yield valuable insights into the mechanisms of leukemic recurrence and may have implications for treatment selection.

Adolescent↗
PubMed1987

A t(8;14)(q24;q32) in a T-lymphoma/leukemia of CD8+ large granular lymphocytes.

Chromosome studies in a case of T cell lymphoma/leukemia, in which a high proportion of the dividing cells had a t(8;14)(q24;q32) similar to that seen in Burkitt's lymphoma, are described. The tumor cells had a mature T cell phenotype (TdT-,CD3+,CD8+,CD4-) and were morphologically large granular lymphocytes and immunoblasts, both cell types with similar lysosomal granules in the cytoplasm. The immunoglobulin heavy chain gene and the T cell receptor beta chain gene were not rearranged, while the T cell receptor gamma chain gene was polyclonally rearranged. Mitoses were obtained only from spontaneously dividing cells in the absence of mitogens; 49 of the 50 metaphases analyzed were chromosomally abnormal and had a t(1;22)(q12;q13) and dup(1)(q31q32) in all of them; 48 metaphases had in addition a t(8;14)(q24;q32) which presumably arose during clonal evolution. The latter may be associated with the aggressive behavior of this T cell disorder by comparison with other proliferations of large granular lymphocytes. Although abnormalities involving 14q32 are characteristic of B cell disorders, they have also been described in T cell malignancies, suggesting that genes transcribed in T cells and/or oncogenic sequences significant in T cell neoplasia are present in 14q32.

Adult↗
PubMed1988

More than two immunoglobulin heavy chain J region genes in the majority of infant leukemia.

Congenital and infant leukemia are rare conditions associated with a very poor prognosis due to the high frequency of adverse clinical and laboratory parameters. As the occurrence of multiple immunoglobulin heavy chain hybridization band in childhood leukemia has been associated with poor prognosis, we studied whether it was present in this type of leukemia as well. Seven cases were examined, 4 of them less than 7 months of age. The immunophenotype was lymphoid in 5 and hybrid in 2. Most had abnormal karyotypes. In 5 of the 7, including all with congenital leukemia, an immunoglobulin heavy chain J region multiband pattern was found by Southern blot. The multiband pattern, whether primary or due to clonal evolution, seems to be associated with poor prognosis.

Adolescent↗