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PubMed1992

[Recent advances in the etiopathology of chronic B-lymphocytic leukemia].

Considerations to multistep development of B-lymphocytic chronic leukaemia are presented under the following aspects: experimental in vitro cultures of bone marrows B lymphocyte precursors, polyclonal nature of proliferating B lymphocytes in the early stage of CLL, especially in the autoimmune status, the role of viruses, the effect of nonrandom chromosome abnormalities and associated alterations in gene functions, clonal evolution during terminal stages of CLL.

Cells, Cultured↗
PubMed1992

Clonal characteristics of acute lymphoblastic cells derived from BCR/ABL p190 transgenic mice.

The clonal and immunophenotypic characteristics of blood leukemic cells from BCR/ABL p190 transgenic mice were investigated. All cell populations evaluated in vivo and in vitro had B-lymphocyte progenitor immunophenotypes. Immunoglobulin (JH) rearrangement patterns provided evidence for clonal diversification at different sites in vivo. Multiple clones were established in vitro from two of these mice (nos. 730 and 753). These cells expressed BCR/ABL p190 protein tyrosine kinase (PTK) and were highly malignant on transfer to secondary recipients. Cells independently cloned in vitro shared identical immunophenotypes and clonal IgH rearrangements, but these were distinct from those of the dominant clones in the mouse from which they were derived. Nevertheless, in vitro clones from mouse no. 753 had an abnormal karyotype (chromosome 14 trisomy) in common with the dominant clone in blood, providing evidence for a hierarchy or clonal selection in vivo and in vitro. Two sets of in vitro clones proliferated independently of exogenous growth factors and stroma and released autocrine interleukin 7 growth factor activity. These data provide evidence for rapid divergent clonal evolution and selection of B-cell progenitors initiated by BCR/ABL p190, followed by other, secondary genetic events mirroring similar changes in the equivalent, highly malignant human leukemia Philadelphia (Ph)-positive/B-precursor acute lymphoblastic leukemia (ALL).

Animals↗
PubMed1992

Antigen selection in human lymphomagenesis.

Although surface immunoglobulin plays a central role in the differentiation and growth of normal B-cells, its role in the growth of human B-cell malignancies is largely a matter of conjecture. Human follicular lymphomas are attractive systems to study in part because they are clones of cells sharing many similarities with germinal center B-cells which are critically dependent on antigen selection for survival. Nucleotide sequence information was determined for the immunoglobulin heavy chain variable genes expressed by two cases of follicular lymphoma. In addition, the germ line variable gene counterparts were also cloned and sequenced from biopsy material obtained from both of these patients. Numerous mutations from germ line were present in the variable genes from both of these cases, many of which accumulated during expansion and growth of these lymphomas. Moreover, the mutations that accumulated during tumor expansion were distributed in a manner that almost certainly was dependent on positive selection presumably mediated by contact with an antigen. These data indicate that antigen selection is probably important for the growth and clonal evolution of follicular lymphomas.

Antigens, Neoplasm↗
PubMed1992

[Refractory anemia with 5q--anomaly. Clinical picture and follow-up of seven patients].

The clinical picture and the course of the disease of seven patients with the 5q-syndrome are described. Examination of peripheral blood revealed refractory anaemia with macrocytosis, anisocytosis, poikilocytosis of erythrocytes, and platelet anisocytosis with some giant platelets. Characteristic bone marrow findings are megaloblastic dyserythropoiesis and micromegakaryocytes with hypolobulated nuclei. Cytogenetically, an interstitial deletion of the long arm of chromosome 5 is always found, associated with a haploid loss of the genes for the growth factors GM-CSF, M-CSF and IL-3. The disease is usually chronic, and only in the case of clonal evolution is there a considerable risk of leukemic transformation occurring. In the chronic phase, infusion of packed red cells as required individually has proved a reliable form of treatment. The results of chemotherapy have disappointed both in the chronic and acute phases of the disease.

Adult↗
PubMed1992

Alternative models for early onset of childhood leukaemia.

This paper considers theoretical models for early-onset childhood leukaemia. The major focus of attention is the two-hit mutational model. A simple mathematical representation is used to explore mechanisms which might lead to onset of leukaemia at an unusually early age. Two such mechanisms are considered. The first of these, a germinal or very early embryonic first mutation is shown to imply that multiple independent leukaemic clones are likely to arise sequentially in very young patients. Clonal multiplicity could underlie the poor prognosis which has been associated with early onset childhood acute lymphoblastic leukaemia. It implies that curative therapy might require intensive treatment followed by bone marrow rescue to ensure eradication of all single-hit predisposed target cells. The prediction of multiple leukaemic clones might be tested in female patients by means of X-linked restriction fragment length polymorphisms and in patients with B-lineage neoplasms by determination of immunoglobin gene rearrangements. A second mechanism for early onset leukaemogenesis is the occurrence of a high cellular mutation rate in some patients. This is shown to result in leukaemia at significantly earlier age if the mutation rate is sufficiently high to influence target cell loss rate. This mechanism would enable more rapid clonal evolution of leukaemic cells and the early emergence of drug resistant variants. The prediction might be tested experimentally by sequential observation of genetic markers (e.g. Karyotypes, DNA fingerprint patterns) and the rate of emergence of drug resistant phenotypes. Other models, considered more briefly, include one-hit mutational 'dominants' in the developing embryo and faster growth kinetics in neoplasms of younger patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Division↗
PubMed2004

Mammary tumor heterogeneity in wt-ErbB-2 transgenic mice.

Phenotypic and biological heterogeneity was studied in a single transgenic mouse model to determine the level of biological variance. We analyzed 1,258 tumors from 417 MMTV-wt-ErbB-2 transgenic mice, subdivided by casein or soy-based dietary randomization and hormonal treatment. Variance in tumor histologic features, growth pattern, invasion, metastases, and multi-focality were detected in untreated and treated mice. Ninety-three percent (1,174/1,258) of tumors had the solid growth pattern widely reported in this model. However, among the solid tumors, a spectrum of growth patterns, from well-circumscribed tumors with a pseudocapsule to locally invasive or highly aggressive, metastatic subtype, was observed. Of the non-solid tumors, glandular features were prominent in 84 (7%). Adenocarcinomas included papillary, acinar/glandular, and adenosquamous subtypes. Adenosquamous tumors were exclusively observed in the group of mice treated on a short-term basis with estrogen. In contrast to the reported literature for this transgenic mouse model, mammary tumors were multifocal in the majority of cases (303 of 417 mice, or 73%). Results of this extensive study of a single transgenic model of mammary tumorigenesis indicate phenotypic and biological heterogeneity not previously associated with this transgenic mouse. These data support a complex, multistep process of carcinogenesis and clonal evolution, with biological and phenotypic variance similar to that observed in human mammary cancer development.

Adenocarcinoma↗
PubMed2004

Coexistence of tetrasomy 8 and trisomy 8 in acute promyelocytic leukemia (AML-M3) with t(15;17)(q22;q12).

This study was purposed to characterize the first case of acute promyelocitic leukemia (AML-M(3a)) with t(15;17), trisomy 8 and tetrasomy 8, and explore its characteristics of morphology, cytogenetics, molecular biology, immunology and clinical features. Morphological changes of peripheral blood and bone marrow smears were observed under microscope. Chromosome specimen was prepared by 24 h short-term culture of bone marrow cell, RHG-banding technique was used for karyotypic analysis. PML-RARa fusion gene transcript was detected by nested-reverse transcription-polymerase chain reaction (nested RT-PCR). Interphase fluorescence in situ hybridization (FISH) using chromosome 8 centromere specific probe were carried out to detect abnormal numbers of chromosome 8. Immunophenotypic analysis was performed by flow cytometry. The results showed that peripheral blood smear revealed 65% promyelocyte, and bone marrow aspirate was hypercellular with 72.4% promyelocyte, moderately basophilic cytoplasm with numerous azurophilic granules. Karyotype analysis demonstrated 48, XY, +8, +8, t(15;17)(q22;q12) [16]/47, XY, +8, t(15;17)(q22;q12) [3]/46, XY, t(15;17)(q22;q12) [1]. RT-PCR assay revealed PML-RARa fusion gene transcript (+). FISH showed that the percentages of cells exhibiting 1, 2, 3, 4, 5, 6 green fluorescence signals were 0.5, 7, 19, 55, 18 and 0.5, respectively. This confirmed the presence of tetrasomy 8 and trisomy 8 and also revealed a low percentage of a pentasomy 8 clone. Immunophenotypes of the blasts displayed that CD13 (96.2%), CD33 (55.9%), CYMPO (93.5%) were positive. All the lymphoid markers tested were negative. The patient survival time was just 10 days. It is concluded that tetrasomy 8 is secondary cytogenetic event after t(15;17) in this case. It may be a consequence of clonal evolution of trisomy 8. t(15;17) AML-M(3) with tetrasomy 8 heralds a poor prognosis.

Chromosomes, Human, Pair 15↗
PubMed2004

Complex variant Philadelphia translocation involving the short arm of chromosome 9 in a case of chronic myeloid leukemia.

Here we describe how we detected the BCR/ABL fusion gene on the short arm of der(9) combining classical GTG banding and Fluorescence In Situ Hybridization (FISH) in a case of chronic myeloid leukemia (CML). To our knowledge, variant translocations involving the short arm of chromosome 9, in literature, are almost rare in chronic myeloid leukemia. It is not clear if this complex genetic translocation represents clonal evolution or a unique, initial presentation variant of the Philadelphia chromosome (Ph).

Adult↗
PubMed1992

Detection of minimal residual disease in acute leukemia by immunological marker analysis and polymerase chain reaction.

Detection of minimal residual disease (MRD) can be useful for adaptation or stratification of treatment in acute leukemia patients and may finally result in individualization of treatment protocols. Although leukemic cells generally have immunophenotypes comparable to their normal counterparts, it is possible to use immunological marker analysis for the detection of MRD based on the assumption that the presence of positive cells outside their normal breeding sites and 'homing areas' is indicative of malignancy. This approach can be used for the detection of MRD in blood and bone marrow of patients with a terminal deoxynucleotidyl transferase (TdT) positive T-cell acute lymphoblastic leukemia (ALL) and patients with a TdT+ acute myeloid leukemia (AML) as well as in cerebrospinal fluid of patients with a TdT+ leukemia. In other types of acute leukemias, immunological marker analysis generally does not allow detection of low frequencies of malignant cells, but in a part of them the polymerase chain reaction (PCR) technique may be valuable. The PCR technique allows the amplification of tumor-specific DNA sequences or mRNA sequences (after reverse transcription into cDNA), if the flanking sequences are well-defined. This PCR-mediated amplification can detect specific sequences which are derived from only a few malignant cells between many normal cells. Well-defined chromosome translocations have been used as tumor-specific markers, such as t(9;22). An advantage of using specific chromosome aberrations as tumor-specific markers is their stability during the disease course. However, only 10-15% of ALL and 25-30% of AML have a specific chromosome translocation and in a large part of them the precise breakpoints are not (yet) known. Recent studies indicate that it is possible to detect MRD in acute leukemias by use of PCR-mediated amplification of the junctional regions of rearranged immunoglobulin (Ig) and T-cell receptor (TcR) genes, using variable (V) and joining (J) gene-specific oligonucleotides as primers. Major pitfalls of this application are the occurrence of multiple rearrangements at diagnosis (oligoclonality) and changes in rearrangement patterns at relapse (clonal evolution), which will lead to false negative results of this MRD-PCR technique. In conclusion, the technique of choice for the detection of MRD is dependent on the immunophenotype of the leukemia, the presence of a well-defined chromosome translocation and the presence of a rearranged Ig and/or TcR gene as well as the chance of immunophenotypic shifts and changes in Ig and TcR gene rearrangement patterns.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1992

[Complex chromosome aberrations between no. 17 and no. 21 in acute myelo-megakaryocytic leukemia: a case report].

A 10 month-old boy presented with fever. He was diagnosed as having acute myelo-megakaryocytic leukemia by electron microscopic cytochemical examination. In spite of aggressive chemotherapy, complete remission could not be achieved and he died seventeen months after the diagnosis was made. G-band karyotypes of the bone marrow cells revealed 45, XY, -17, -21, + dir tan dup (17;21) (17pter----cen----17q25::17q21----17q25;21q11 ----21qter). Furthermore, the same chromosomal aberrations were detected in the cells which were tetraploid and octaploid. Although, neoplastic changes in the progenitor cells immediately before differentiating to CFU-Meg and CFU-GM, are suggested there is a possibility of clonal evolution.

Chromosome Aberrations↗
PubMed1992

Serial cytogenetic studies in allografted patients with chronic myeloid leukemia.

Serial marrow karyotyping was performed in 31 chronic myeloid leukemia (CML) patients treated with allogeneic bone marrow transplantation (BMT). Of 11 hematological relapses, seven were heralded for up to 20 months by a cytogenetic relapse (characterized by increasing percentages of Philadelphia (Ph)-positive metaphases, seen on serial karyotypes). Chromosomal abnormalities additional to the Ph, seen before BMT, were not found again at relapse. Relapses were characterized by clonal evolutions of the Ph-positive cells, likely corresponding to cytogenetic patterns of treatment-induced leukemia [del(5q), del(7q), complex karyotypes] and were different from those generally found in CML evolution. Involvement of chromosome 1 was also frequent. Sporadic Ph-positive metaphases (not seen in repeated karyotypes) were seen only during the first 8 months after BMT.

Adolescent↗
PubMed2005

[Molecular genetic methods for the prognostic criteria in multiple myeloma].

Routine cytogenetic and molecular genetic analysis of plasma cell malignancies, such as multiple myeloma, became widespread only recently. As the result of these investigations, it became clear that tumor cell karyotype is fundamental from the viewpoint of therapy selection and prognosis. It is worthwhile to distinguish hyperdiploid and nonhyperdiploid myeloma, while five separate prognostic groups (TCI-5) may be identified on the basis of immunoglobulin gene translocations and cyclin expression. Deletion of the q arm of chromosome 13 or amplification of region 1q21 (and the CKS1B gene) can identify further subgroups of poor prognosis and few therapeutic options. Meanwhile, tumors harboring translocation t(11;14) respond favorably to conventional chemotherapy and exhibit exceptionally good and long-lasting response to high-dose chemotherapy. Progression of the disease may coincide with complex translocations of the c-myc gene or deletions involving the p53 tumor-suppressor gene, spreading of ras-mutations. These events represent clonal evolution at great tumor cell mass and advanced disease, therefore, are only of secondary prognostic significance.

CDC2-CDC28 Kinases↗
PubMed1992

[Germinal tumors of the mediastinum. Therapeutic strategy, prognosis, biology].

Mediastinal germ cell tumors have a poor prognosis. Cisplatin containing chemotherapy combined with either primary or post-chemotherapy exeresis of the disease can induce a 50% cure rate. Acute leukemia is often associated with these tumors. In these cases, a clonal evolution from the germ cell tumor has been demonstrated.

Biomarkers, Tumor↗
PubMed1992

[Microspectrophotometric analysis of DNA content in duct epithelial proliferation and invasive carcinoma of the pancreas].

Nuclear DNA content of 131 pancreatic duct epithelial lesions, including 10 normal ducts, 30 intraductal proliferations with mild atypia (groups I-II), 30 with moderate atypia (group III), 24 with severe atypia (group IV), 14 of carcinoma in situ (group V), and 23 invasive carcinomas, was analyzed using microspectrophotometry. DNA histograms were classified into diploid, polyploid and aneuploid patterns. All of normal duct epithelia showed diploidy. Polyploid patterns were observed in 3 (10%) lesions of groups I-II, 17 (56.7%) of group III, 14 (58.4%) of group IV, 7 (50%) of group V, and 6 (26.1%) of invasive carcinomas, and aneuploid patterns were observed in 0%, 10%, 33.3%, 50% and 73.9%, respectively. This distribution of ploidy patterns revealed a gradual shift to the main ploidy from diploid to polyploid followed by aneuploid in proportion to the increase of the degree of epithelial atypia. The frequencies of polyploid cells in each lesion were determined. Their averages were 0.2% in groups I-II, 1.9% in group III, 3.4% in group IV, 4.4% in group V, and 6.7% in invasive carcinoma. The S+G2M phase fractions were significantly higher in proliferative epithelia than in normal. The results of this study suggest that duct epithelial proliferations of the pancreas have "genetic instability" leading to a serial clonal evolution and play a significant role in the progression of pancreatic duct cell carcinoma.

Carcinoma in Situ↗
PubMed1991

Genetic analysis of germ cell tumors: current progress and future prospects.

Cytogenetic analysis of germ cell tumors (GCTs) has identified i(12p) as a specific cytogenetic abnormality identified in more than 80% of GCTs, present in all histologies, in primary and metastatic lesions, in testicular and extragonadal presentations, and in ovarian and sex cord stromal tumors. Other nonrandom numeric and structural chromosomal abnormalities have also been identified. Oncogene studies suggest a potential role for n-ras mutations in GCT transformation. The role of loss of tumor suppressor genes and increased genomic dosage of growth promoter genes remain areas of great interest. Leukemias and differentiated malignancies that arise in the setting of GCT appear to be clonally derived from GCT cells, with evidence of karyotypic progression and acquisition of other tumor-specific cytogenetic markers. Identification of i(12p) in poorly differentiated midline carcinomas of uncertain histogenesis can assist in the diagnosis of GCT. The presence of three or more copies of 12p may predict resistance to chemotherapy and portend a higher likelihood of treatment failure. Future cytogenetic studies in GCT promise to provide insight into the biology and treatment of all solid tumors, because GCTs are a model of chemotherapeutic responsiveness, cellular differentiation, and tumor clonal evolution.

Cell Differentiation↗
PubMed2006

Microdissection-based allelotyping: a novel technique to determine the temporal sequence and biological aggressiveness of colorectal cancer.

Pathologic staging in colorectal adenocarcinoma (CA) is based on the concept that the timing of metastatic tumor spread is directly related to the depth of the primary tumor invasion. To evaluate the temporal sequence of CA metastasis, we performed microdissection mutational profiling at multiple microscopic sites of primary and metastatic CA specimens. Twenty-one cases of CA were selected from fixed-tissue archives. Primary tumors were microdissected at the deepest point of invasion. Comparative mutational profiling for different genomic loci [1p36(CCM = cutaneous malignant melanoma], 3p26(OGGI = 8 oxoguanine DNA glycosylase), 5q23 (APC, MCC = mutated in colorectal cancer), 9p21(p16/CDKN2A = cyclin-dependent kinase 2A), 10q23(PTEN = phosphatase and tensin homolog [mutated in multiple advanced cancers 11), 12p12(K-ras-2 point mutation), 17p13(TP53), 18q25(DCC= deleted in colorectal cancer) was carried out on each microdissected tissue target using microsatellite loss of heterozygosity determination or DNA sequencing. All primary and metastatic sites of CA manifested acquired mutational change in 18 to 91 per cent of the genomic markers. In 15/21 (71%) cases, metastatic sites lacked a specific allelic loss seen in the corresponding primary tumor, indicating that the metastasis occurred before maximal depth of primary invasion. This was further supported by discordant mutational profiles between primary and secondary tumors, requiring divergent clonal evolution. This is the first report describing the temporal sequence and significance of sequential mutational acquisition in clinical tissue specimens with potential implications for a new molecular pathology approach to classify human cancer.

Adenocarcinoma↗
PubMed2006

[Indications of G-CSF administration in hematologic disorders].

Granulocyte colony stimulating factors (G-CSF) are largely used in the treatment of hematologic disorders to improve both the myelosuppression which might directly result from the disease or indirectly induced by the numerous chemotherapy regimen. G-CSF reduces the depth and duration of neutropenia in lymphoma patients and thus allows the design of more dose intense chemotherapy regimen which were shown to improve outcome particularly in patients with diffuse large B-cell and Hodgkin's lymphoma. G-CSF has been studied in patients with acute leukemias (ALL and AML) both concomitantly to induction chemotherapy to sensitize leukemic cells and after chemotherapy to reduce the duration of neutropenia and incidence of severe infection but it's benefit in these settings is still controversial. Myelodysplastic syndromes (MDS) can benefit from G-CSF in association with erythropoietin, particularly for patients with relative good prognosis according to the IPSS score at diagnosis. Still, an improvement of Quality of life needs to be demonstrated in the vue of the cost of these strategies. In aplastic anemia (AA), G-CSF has been used as a support during infection or in association with immunosuppressive treatments but caution is needed regarding the risk of clonal evolution in AA. The benefit of low dose G-CSF in chronic severe neutropenia is well established but the long term consequences of continuous G-CSF support are not known. Finally, G-CSF given alone or after chemotherapy as become one of the key components of hematopoietic stem cell mobilization allowing the use of high dose therapies with autologous or allogeneic stem cell support.

Granulocyte Colony-Stimulating Factor↗
PubMed1990

[Cytogenetic and clinical features of Philadelphia chromosome positive leukemias].

The Philadelphia chromosome defines chronic myeloid leukemia, and is mostly based on a translocation t(9;22) with a typical BCR-ABL rearrangement which also occurs in so called atypical translocations. The transformation of chronic myeloid leukemia is associated with clonal evolution in 80% of cases. The appearance of an isochromosome 17q unequivocally heralds the onset of a myeloid type of blast crisis. Treatment of Ph-positive CML has still to be considered palliative except for allogeneic bone marrow transplantation. The Philadelphia chromosome is also found in about 20% of patients with acute lymphoblastic leukemia and in about 2% of patients with nonlymphoblastic leukemia. It is associated with a poor prognosis. Molecular and cytogenetic findings help differentiating between de novo acute leukemia and blast crisis of chronic myeloid leukemia.

Blast Crisis↗