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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombocytosis is a characteristic clinical feature in patients with myelocytic malignancies and chromosomal rearrangements of 3q21 and 3q26, sometimes called the '3q21q26 syndrome'. The function of thrombopoietin (TPO) in megakaryocytopoiesis and thrombopoiesis as well as its chromosomal location, marked TPO as a candidate gene for malignancies with 3q rearrangements combined with dysmegakaryopoiesis. In this study 12 cases with inv(3)(q21q26) or t(3;3)(q21;q26) were analyzed by means of PFGE, but no rearrangements near the TPO locus were detectable. Six YACs containing the TPO locus were isolated and characterized. By dual color in situ hybridization using a YAC from 3q26 containing the EVI1 gene and a YAC from the TPO locus, the localization of the human TPO gene could be refined to 3q27-q28 about 15-20 Mbp telomeric to the 3q26 breakpoints occurring in myeloid malignancies. TPO levels were analyzed in the serum of three patients and were found to be in the normal range. These results confirm the findings of two previous studies that thrombopoietin expression is not the main cause of thrombocytosis in the 3q21q26 syndrome.
Leukemia 1996 Dec
PMID:Refined chromosomal localization of the human thrombopoietin gene to 3q27-q28 and exclusion as the responsible gene for thrombocytosis in patients with rearrangements of 3q21 and 3q26. 894 27

The CAS (cellular apoptosis susceptibility) gene is the human homolog of the yeast chromosome segregation gene CSE1. CAS may have a dual function in mammalian cells, one in apoptosis and another in cell proliferation. We have now mapped the CAS gene to chromosome 20q13. This region is known to harbor amplifications that correlate with aggressive breast cancer. Southern hybridizations with a CAS cDNA fragment and fluorescent in situ hybridization (FISH) with a P1 clone containing the CAS gene show elevated copy numbers in one leukemia, three of four colon, and in three of seven breast cancer cell lines. Elevated CAS copy number in CEM leukemia and COLO201 colon cancer cells was attributable to additional copies of chromosome 20. In SW480 and COLO205 colon cancer cells CAS is part of aberrant chromosomes containing large parts of 20q. In breast cancer cells CAS is also part of aberrant 20q chromosomes (MDA-MB-157 and UACC-812) or of additional 20q isochromosome in MDA-MB-134. In MDA-MB361 and BT-474 breast cancer cells CAS is separated from other markers centromeric and telomeric of CAS on 20q. MDA-MB 361 contains one additional copy of CAS, separated from the centromeric 20q control probe. BT-474 cells have up to 12 additional CAS copies that we separated from nearby telomeric and centromeric probes on 20q and that are translocated to abnormal chromosomes.
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PMID:The human CAS (cellular apoptosis susceptibility) gene mapping on chromosome 20q13 is amplified in BT474 breast cancer cells and part of aberrant chromosomes in breast and colon cancer cell lines. 896 95

Analysis of mRNA in two haemophilic monozygotic twins offers novel information on the organisation of expressed sequences distal to the coagulation factor VIII gene. These patients show an inversion that, in contrast to the common inversions responsible for 1/5 of all haemophilia A, affects the first rather than intron 22 of the gene. This displaces the most telomeric of the factor VIII exons (exon 1) by approximately 100 kb towards the telomere, and close to the region of the C6.1A gene. This novel inversion creates two hybrid transcription units: one formed by the promoter and first exon of the factor VIII gene followed by a widely expressed sequence; the other by the promoter and coding region of the C6.1A gene plus most of the factor VIII gene (part of intron 1 and exons 2-26). Investigation of this transcription unit reveals that the C6.1A gene has an unsuspected intron in the region coding for the previously described 3'-untranslated tail of the message. Furthermore, exons located beyond the known C6.1A sequence and present in normal transcripts precede exons 2-26 of the factor VIII gene in the hybrid mRNA of the haemophilic twins. The factor VIII sequences in this hybrid mRNA are not expected to be expressed because they lack the first exon, encoding the prepeptide, and follow a translation stop in the C6.1A gene. Leukaemia-related translocations in the C6.1A region suggest that this region may be somewhat unstable.
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PMID:Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia. 896 48

Tetrasomy 8 is a rare clonal anomaly in human acute leukemia. Here we present a case of a 7-year-old boy with acute lymphoblastic leukemia (ALL) displaying a tetrasomy 8 clone that could not be detected by conventional cytogenetics. In this study, bone marrow and peripheral blood cells were collected at five different diagnostic stages and analyzed by double targeted fluorescence in situ hybridization (FISH) with centromeric DNA probes for chromosomes 7, 8, 9, and 12. FISH analysis revealed a significant increase in tetrasomy 8 frequency, but not in other chromosomes examined. A smaller increase in trisomy 8 was also detected. At one stage over 60% of the cells were hyperdiploid with 40% being tetrasomic. The size of the tetrasomic clone changed during the course of the disease. The hyperdiploid frequencies of chromosome 8 detected by interphase FISH analysis in bone marrow and peripheral blood were similar. Our findings indicate the utility of FISH analysis in cytogenetic monitoring of leukemia patients and further show that tetrasomy 8 may play a specific role in a subtype of ALL.
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PMID:Tetrasomy 8 detected by interphase cytogenetics in a child with acute lymphocytic leukemia. 897 70

Fifty-six patients with de novo acute myeloid leukemia M4/M5 subtypes were studied for rearrangements of the mixed lineage leukemia gene, MLL (also called HRX, Htrx-1, or ALL-1). Ten patients (18%) showed rearrangements of the MLL gene, 9 in a major breakpoint cluster region within a centromeric 8.3-kb BamHI fragment, whereas rearrangement in one patient was the result of a direct tandem duplication of exons 2-6 of MLL. Analysis of sequences at the duplication junction revealed that the points of MLL fusion within introns 6 and 1 both lie within Alu elements. This suggests the involvement of Alu repeat mediated homologous recombination in MLL self fusion. For the 10 rearranged samples, cytogenetics analysis revealed a normal karyotype in 3, and 3 had abnormalities other than 11q23. Survival analysis of patients revealed no difference between those with rearrangement of MLL and those showing the germ-line configuration.
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PMID:MLL self fusion mediated by Alu repeat homologous recombination and prognosis of AML-M4/M5 subtypes. 898 51

Progressive telomere shortening is thought to be important in the regulation of cellular senescence and that the upregulation or reactivation of telomerase activity may be a critical if not rate limiting step in the development of neoplastic cells. To obtain information about telomeres and telomerase activity in hematopoietic neoplasia at various disease stages, we evaluated 54 samples obtained from 41 patients with chronic myeloid leukemia (CML) using a combination of fluorescent-telomeric repeat amplification protocol and an internal telomerase assay standard. The terminal restriction fragment (TRF) lengths in the blast phase was reduced compared to that in the chronic phase (4.53 +/- 0.72 kb vs 6.13 +/- 1.68 kb; P = 0.0005). All samples obtained from CML in the chronic phase (n = 33) had detectable telomerase activity above background, regardless of age. In the blast phase (n = 21), a significant increase of telomerase activity was detected compared to that in the chronic phase (33.84 +/- 37.86% vs 6.08 +/- 3.21; P = 0.016). Among patients in the blastic phase, 50% of patients had moderate to high telomerase activity (>10 relative value), and the remaining patients had telomerase activity higher than that in the normal peripheral blood cells. No significant differences in hematologic findings, duration of chronic phase or blast phase, and telomere length in the blastic phase were noted between these two groups separated by telomerase activity. CML patients with moderate to high telomerase activity had a high frequency of additional cytogenetic changes (P = 0.01).
Leukemia 1997 Feb
PMID:Telomerase activity and cytogenetic changes in chronic myeloid leukemia with disease progression. 900 79

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. Details of the molecular mechanisms involved in the pathogenesis of this leukemia are unclear at present. In other malignancies tumorigenesis has been shown to proceed via a multistep progression model with a causal relation between the accumulation of genetic abnormalities and more aggressive clinical behavior. The loss of chromosomal segments in malignant cells has proven useful in mapping regions of DNA that contain candidate tumor suppressor genes. The detection of loss of heterozygosity (LOH) has been greatly facilitated by the analysis of highly polymorphic microsatellite markers enabling the identification of submicroscopic losses. Utilizing immunomagnetic bead sorting to separate leukemic from normal cells we identified at least one allelic losses in 8/29 (28%) of analysed CLL cases with a PCR-based assay. On chromosomal arm 3p we have identified homozygous deletions in 3/29 cases at locus D3S1284 residing in the vicinity of the newly described FHIT gene. Several cases of CLL manifested LOH at a locus telomeric to the p15 and p16 tumor suppressor genes, all being early to intermediate stage disease. Our findings suggest that losses at these loci may contribute to the development and/or progression of CLL in at least a subset of cases.
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PMID:Allelic loss determination in chronic lymphocytic leukemia by immunomagnetic bead sorting and microsatellite marker analysis. 901 24

It has been proposed that telomeres shorten with every cell cycle because the normal mechanism of DNA replication cannot replicate the end sequences of the lagging DNA strand. Telomerase, a ribonucleoprotein enzyme that synthesizes telomeric DNA repeats at the DNA 3' ends of eukaryotic chromosomes, can compensate for such shortening, by extending the template of the lagging strand. Telomerase activity has been identified in human germline cells and in neoplastic immortal somatic cells, but not in most normal somatic cells, which senesce after a certain number of cell divisions. We and others have found that telomerase activity is present in normal human lymphocytes and is upregulated when the cells are activated. But, unlike the immortal cell lines, presence of telomerase activity is not sufficient to make T cells immortal and telomeres from these cells shorten continuously during in vitro culture. After senescence, telomerase activity, as detected by the TRAP technique, was downregulated. A cytotoxic T lymphocyte (CTL) cell line that was established in the laboratory has very short terminal restriction fragments (TRFs). Telomerase activity in this cell line is induced during activation and this activity is tightly correlated with cell proliferation. The level of telomerase activity in activated peripheral blood T cells, the CTL cell line, and two leukemia cell lines does not correlate with the average TRF length, suggesting that other factors besides telomerase activity are involved in the regulation of telomere length.
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PMID:Changes in telomerase activity and telomere length during human T lymphocyte senescence. 908 76

Cytogenetic analysis provides critical information of diagnostic and prognostic importance for haematological malignancies. In fact, the identification of recurring chromosomal breakpoints in leukaemias and lymphomas has expedited the cloning of genes whose translocation-induced deregulation causes malignant transformation. The pillar of karyotype analysis rests on chromosome banding techniques that have the distinct advantage that the entire genome can be analysed in a single experiment. However, poorly spread or contracted metaphase chromosomes and highly rearranged karyotypes with numerous marker chromosomes, common in tumour cell preparations, are often difficult to interpret unambiguously and subtle chromosomal aberrations, in particular the exchange of telomeric chromatin or small insertions remain elusive. Fluorescence in situ hybridization (FISH) overcomes some of these limitations, but is mainly utilized to confirm the presence of previously characterized or suspected aberrations. We have developed a novel approach, termed spectral karyotyping or SKY based on the hybridization of 24 fluorescently labelled chromosome painting probes that allows the simultaneous and differential colour display of all human chromosomes. We have used SKY to complement conventional banding techniques in haematological malignancies by analysing 15 cases with unidentified chromosome aberrations. In all instances SKY provided additional cytogenetic information, including the identification of marker chromosomes, the detection of subtle chromosomal translocations and the clarification of complex chromosomal rearrangements. Thus, SKY in combination with standard chromosome banding allows the characterization of chromosomal aberrations in leukaemia with unprecedented accuracy.
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PMID:Hidden chromosome abnormalities in haematological malignancies detected by multicolour spectral karyotyping. 909 Mar 89

The principle of the fluorescence in situ hybridization (FISH) method is in the base pairing of the DNA probe to complementary sequences in the studied specimen. The hybridization of specific DNA or RNA probes to the cellular targets attached to the microscopic slides is widely used for the identification of chromosomal translocations, deletions, amplifications of specific genes, and chromosome number changes in mitotic and/or interphase cells. The use of FISH with the modifications of the basic method meant a breakthrough in detection and diagnosis of human malignancies. During the last tow years FISH was used in our laboratory for: (a) identification of constitutive and acquired numerical and structural chromosomal abnormalities; (b) detection of minimal residual disease or early relapse in patients treated for leukemia by bone marrow transplantation (BMT) and/or chemotherapy; (c) determination of the cytogenetic pattern of non-dividing or terminally differentiated cells. To confirm the structural rearrangements found by the classical G-banding technique, the whole chromosome painting probes which hybridize to multiple chromosomal sequences were used. The alpha-satellite DNA probes which detect centromeric repetitive sequences were utilized for determining the numerical and sex chromosome changes. Specific unique chromosomal sequences which can confirm all chromosomal rearrangements, i.e., deletions, translocations or inversions with the corresponding breakpoints were introduced for specific cases. Recently, every chromosomal translocation, deletion and any other structural or numerical change found by conventional cytogenetic analysis in the bone marrow cells of the patients with leukemia has been verified in our laboratory by FISH. The results of this study showed that FISH is more efficient than conventional cytogenetics in detecting residual malignant cells. For chromosomal rearrangements FISH is an extremely sensitive method which not only verifies but also interprets with more precision the findings of classical cytogenetics.
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PMID:Fluorescence in situ hybridization (FISH) in cytogenetics of leukemia. 915 41


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