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At least 343 records · Page 19Linked to original sources
PubMed1993

Absence of reverse transcription-polymerase chain reaction detectable residual disease in patients with acute promyelocytic leukemia in long-term remission.

Hybrid fusion genes are specific tumor markers of several leukemic subtypes. The use of reverse transcription-polymerase chain reaction (RT-PCR) to amplify chimeric cDNAs allows sensitive detection of the neoplastic clone for diagnostic and monitoring studies in these leukemias. Nonetheless, the clinical relevance of minimal residual disease (MRD) evaluation by PCR remains controversial. In this study, 9 patients (pts) with acute promyelocytic leukemia (APL) in long-term remission for 4 to 12 years were analyzed for the presence of MRD by RT-PCR amplification of the specific PML/RAR-alpha fusion gene. Seven pts had been treated with conventional chemotherapy (CHT) alone, 1 had undergone allogeneic bone marrow transplantation (BMT), and 1 autologous BMT as consolidation therapy after CHT. In 8 cases, the presence of the t(15;17) rearrangement could be documented in diagnostic BM specimens by cytogenetic and/or molecular analysis. A two-rounds "nested" RT-PCR assay with sensitivity levels of 1 in 10(5) was used to analyze BM samples collected at 32 to 141 months from the achievement of complete remission (CR). In no cases were residual PML/RAR-alpha transcripts detectable in these remission controls. All patients are in unmaintained CR at 48 to 154 months from CR and at 6 to 17 months from PCR evaluation. These results suggest that long-term survival of APL is associated with eradication of cells carrying the specific PML/RAR-alpha rearrangement, indicating that PCR negativity should be considered the therapeutic goal in these patients. Our findings further strengthen the clinical relevance of PCR monitoring studies in APL, as opposite to other leukemic subtypes (chronic myeloid leukemia and acute myeloid leukemia-M2) in which the prognostic significance of PCR evaluation is unclear.

Adult↗
PubMed1993

Molecular analysis of T-cell receptor transcripts in a human T-cell leukemia bearing a t(1;14) and an inv(7); cell surface expression of a TCR-beta chain in the absence of alpha chain.

The polymerase chain reaction (PCR) was used to amplify cDNA in order to characterize normal and hybrid T-cell receptor (TCR) gene rearrangements derived from a T-cell acute lymphoblastic leukemia (T-ALL) bearing a chromosome 7 inversion. The nucleotide sequence analysis of the amplified product showed the presence of an out-of-frame V beta/J gamma/C gamma transcript and an in-frame V gamma/J gamma/C beta transcript which result from an interlocus recombination between the TCR-beta and gamma loci and the transcription of the reciprocal hybrid TCR gene. The sequence analysis of the reciprocal DNA segment directly involved in the breakpoint of the inversion showed a recombination between a J gamma-sequence heptamer signal and a coding J beta gene segment. The exonuclease nibbling of each DNA extremity and the non-templated nucleotide insertion observed at both coding and reciprocal joints demonstrate that the inversion is mediated by the lymphocyte recombinase complex. During T-cell differentiation, TCR-beta genes are rearranged prior to TCR-alpha genes. In the present case of T-ALL, we have shown that TCR-delta genes are rearranged at both loci, excluding productive rearrangements of TCR-alpha genes. The molecular analysis of the normal TCR genes derived from the leukemic cells revealed the presence of productively rearranged TCR-beta, gamma, and delta genes. Cell surface staining of these cells showed the presence of CD3 molecules and of a TCR-beta chain corresponding to the normal beta allele expressed in a disulfide-linked complex with a protein which is not TCR-alpha, gamma, or delta. This could represent the cell surface expression of the hybrid TCR-V gamma/C beta protein or the expression of a TCR-beta homodimer.

Adult↗
PubMed1993

RT-PCR detection of mRNA recovered from archival glass slide smears.

This manuscript describes a protocol for the utilization of glass slide preparations of hematologic specimens for the recovery of mRNA that is of a quality suitable for the reverse transcription-polymerase chain reaction (RT-PCR) detection of specific gene expression. Total cellular RNA obtained from archival bone marrow aspirate smears of 23 leukemia patients, which had been stored for periods of time from 1 day to 34 mo, were extracted, and 1 to 2 micrograms of each were subjected to RT-PCR using primer pairs specific for the amplification of beta-actin cDNA. Three pairs of primers for the amplification of beta-actin cDNAs of 83,260, and 540 base pairs were used to evaluate the length of mRNA that could be analyzed; the results indicate the consistent amplification of cDNA for the short- and intermediate-sized fragments as revealed by ethidium bromide fluorescence of agarose gel-resolved PCR products. To address the utility of RT-PCR analysis towards the detection of mRNA associated with specific gene alterations in such specimens, a primer pair for amplification of the E2A-PBX1 fusion cDNA was used in PCRs of RT cDNAs for each of the 23 specimens, three of which were pre-B-cell acute lymphoblastic leukemias known to have the t(1;19) karyotype alteration resulting in the fusion of the E2A and PBX1 genes. Agarose gel electrophoresis analysis of the products of these RT-PCR amplifications revealed the amplification of the fusion gene cDNA in only those cases for which there was cytogenetic documentation of t(1;19); these results were confirmed by the Southern filter hybridization of an internal E2A-PBX1 oligonucleotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1993

[Importance of mutations interfering with mouse development].

In the mouse several point mutations and a great variety of chromosomal rearrangements are available. They all represent useful tools for experimental studies in developmental biology. This review provides, with the help of a few examples, an overview of the importance of the mouse for studies of the genetics of mammalian development.

Animals↗
PubMed1993

Some recent aspects of the molecular biology of human lymphoma.

Some recent aspects of the molecular biology of chromosome abnormalities that activate the BCL2 gene in B cell malignancies (follicular lymphoma, chronic lymphocytic leukemia) are discussed. We also report data showing that the Epstein-Barr virus (EBV) LMP-1 protein which can induce the expression of BCL2, is found infrequently in follicular lymphomas which exhibit no apparent BCL2 gene rearrangement.

Antigens, Viral↗
PubMed1996

Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11;17)-associated acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) associated with chromosomal rearrangement t(11;17) is a distinct syndrome which, unlike typical t(15;17) APL, fails to respond to all-trans retinoic acid (ATRA) therapy. In t(11;17) the PLZF gene, encoding a Krüppel-like zinc finger protein, is fused to the retinoic acid receptor-alpha (RAR alpha) gene, yielding two classes of chimeric proteins. PLZF protein was found in the nucleus in a punctate speckled pattern that differed from the nuclear body expression pattern of the PML protein affected in t(15;17) APL. The reciprocal PLZF-RAR alpha and RAR alpha-PLZF fusion proteins were localized to the nucleus both in the presence and absence of ATRA. PLZF-RAR alpha, in combination with the retinoid X receptor (RXR) bound to a retinoic acid-responsive element (RARE) less efficiently than RAR alpha and formed multimeric DNA-protein complexes. PLZF-RAR alpha stimulated ATRA-dependent transcription of RARE-containing reporter genes with diminished activity compared to wild-type RAR alpha. In addition, PLZF-RAR alpha antagonized the function of coexpressed wild-type RAR alpha, an effect relieved by over-expression of RXR. Leukemogenesis in t(11;17) APL may be related to interference with ATRA-mediated differentiation due to sequestration of RXR by the PLZF-RAR alpha chimera. However, disruption of the function of the myeloid-specific PLZF protein may also play an important role.

Base Sequence↗
PubMedDate not supplied

Regulation of TNF-alpha and IL-1 gene expression during TPA-induced differentiation of "Malignant histiocytosis" DEL cell line t(5;6) (q35:p21).

The production of TNF-alpha and IL-1 alpha and beta molecules has been shown to be associated with the proliferation and activation of cells of the monocyte/macrophage series, the intermediate steps in the synthesis of these molecules have been less investigated. Unstimulated and TPA stimulated DEL cells (a CD30-positive, t(5;6)(q35;p21) malignant histiocytosis cell line) were used to study the expression of TNF-alpha and IL-1 genes and to evaluate, by nuclear run-on assay and biological measurements, the control of their transcription and the level of protein production. To refine this analysis, the effects of cycloheximide and actinomycin D were also evaluated in this investigation. Following TPA stimulation, transcription of TNF-alpha (constitutively present) increased threefold as early as 30 mins and started decreasing by 24h. Cycloheximide superinduced the expression of TNF-alpha mRNA and, accordingly, the release of its protein. By contrast, transcription of IL-1 molecules appeared de novo and did not result in a biologically detectable protein. Measurements of RNA half line after actinomycin D indicated that TNF-a and IL-1 alpha mRNAs are not as stable as that of IL-1 beta. These results indicate that, despite their common synergistic activity, the transcriptional and post-transcriptional mechanisms regulating the synthesis of TNF-alpha and IL-1 alpha and IL-1 beta involve different pathways.

Blotting, Northern↗
PubMed1996

Expression of the LH2 gene in chronic myeloid leukaemia cells.

The LH2 gene encodes a putative transcription factor containing two N-terminal LIM and one C-terminal HOX domains. The LH2 locus was mapped to 9q33-34.1, centromeric to the ABL gene. In a recent report, it was suggested that high levels of LH2 expression are consistently observed in chronic myeloid leukemia (CML) patients, whereas no transcription is detected in normal individuals. This led to the hypothesis that aberrant expression of LH2 may represent an additional mechanism for malignant cell proliferation in CML. We have studied the expression of LH2 in leucocytes from patients with CML or with other chronic myeloproliferative disorders (CMD), and from normal individuals, using an optimised reverse-transcription and polymerase chain reaction (PCR) technique. Twenty-seven out of 29 cDNA samples from normal individuals (93%), 49 out of 51 samples from CML patients (96%) and 20 out of 20 from Philadelphia chromosome-negative CMD showed evidence of LH2 expression. Similarly, LH2 transcription was also detected in leucocytes from CML patients in complete cytogenetic remission after treatment with interferon-alpha. Furthermore, all 36 EBV-induced lymphoblastoid cell lines established from six chronic phase CML patients showed unequivocal LH2 expression, regardless of the BCR-ABL status of the line (9 BCR-ABL positive, 27 BCR-ABL negative). We conclude that LH2 expression is not confined to CML cells, and that the t(9;22)(q34;qll) does not promote 'de novo' transcriptional activation of this gene.

Base Sequence↗
PubMed1996

Detection of PML-RAR alpha in patients with APL during follow-up period.

OBJECTIVE: To evaluate the significance of PML-RAR alpha transcripts in patients with acute promyelocytic leukemia (APL) during remission period and to follow up the patients through monitoring aberrant gene expression. PATIENTS AND METHODS: This study included 17 patients with APL (5 females and 12 males). Another 19 APL patients during relapse served as control. RNA extraction was obtained through the single-step method. By means of reverse transcriptase polymerase chain reaction (PCR), the PML-RAR alpha was detected in the sample mRNA. RESULTS: Nine out of 10 patients with complete remission (CR) duration shorter than 3 years were positive. Four cases became negative and three remained positive among 7 cases in a long remission of over 3 years. The difference of the positive rate of PML-RAR alpha transcripts between the 2 groups was significant (P < 0.05). Four among 12 positive cases relapsed. No evidence of relapse was present in the 5 negative patients after 9.6 +/- 3.9-month follow-up. Further treatment was therefore given to the 4 positive patients whose treatment was already ceased at that time. By this management they were all in CR during the following 10-month observation. CONCLUSIONS: RT-PCR detection for PML-RAR alpha transcripts was useful in monitoring MRD and guiding further treatment to obtain a long remission. Persistently positive transcripts were closely associated with the relapse.

Adolescent↗
PubMed1995

Transformation of follicular lymphoma with both t(14;18) and t(8;22).

The majority of low grade non-Hodgkin's follicular lymphoma undergo clinical progression to intermediate and high grade lymphoma, but the molecular mechanisms involved in this transformation are not yet well understood. In this article, we describe the case of a 66 year old man with follicular non-Hodgkin's lymphoma (NHL), in whom a centroblastic leukaemic transformation led to death in six months, despite a transient period of remission. At the time of transformation, cytogenetic analysis revealed the original coexistence of t(14;18)(q32;q21) and t(8;22)(q24;q11). These results were confirmed by fluorescent in situ hybridization, while molecular analysis showed a BCL2-JH rearrangement but failed to detect a c-myc rearrangement or any additional p53 mutation. Our observations would therefore suggest other mechanisms to be involved in the transformation of follicular NHL.

Aged↗
PubMed1997

Contrasting effects of PNA invasion of the chimeric DMMYC gene on transcription of its myc and PVT domains.

A peptide nucleic acid (PNA) complementary to a unique DNA sequence in the second exon of the human myc proto-oncogene was tested for its effects on transcription in colonic adenocarcinoma cells in which myc had been amplified and rearranged. A prominent rearrangement in this human cell line (COLO320-DM) involves the insertion of exon 1 of the PVT gene, which is normally located 57 kb downstream, into the first myc intron. We compared the effects of PNA invasion of the resulting chimeric gene (DMMYC) on sense and antisense transcription of its myc and PVT domains. Run-on transcription experiments showed that PNA binding to the unique myc sequence was highly specific and strongly inhibited sense transcription of four unique myc sequences downstream of the PNA.DNA hybridization site, the extent of inhibition at each sequence depending on the duration of exposure to PNA, and the distance between the downstream myc sequence and the PNA block. The same PNA also inhibited antisense transcription of unique myc sequences upstream of the binding site, confirming that transit of the RNA polymerase II complexes was impaired in both directions. The inhibitory effect of PNA on upstream antisense transcription extended beyond the recombination site into the contiguous PVT domain of the chimeric DMMYC gene. In contrast, the same PNA did not inhibit PVT transcription in a cell line (Raji lymphoma) in which PVT rearrangement did not involve the myc locus.

Adenocarcinoma↗
PubMed1996

Abnormal expression of Evi-1 gene in human leukemias.

The human Evi-1 gene located on chromosome 3q26, encodes a zinc finger protein that functions as a transcription factor. It was frequently overexpressed in leukemias having 3q26 abnormalities such as t(3;3)(q21;q26) and inv(3)(q21 q26), and subjected to structural alteration in t(3;21)(q26;q22). In addition, recent studies indicated that several cases of leukemias without 3q26 abnormalities also expressed Evi-1 gene. In this study we present another case of structural alteration of Evi-1 gene in a case of inv(3)(q21 q26), in which Evi-1 was truncated and a shorter form of Evi-1 protein was expressed upon rearrangement of the gene. We also studied expression of the Evi-1 gene in a variety of leukemias by northern blot analysis. Evi-1 was overexpressed not only in leukemias with 3q26 abnormalities, but, in those without 3q26 abnormalities, especially in blast crisis of CML. Our result also supports an idea that Evi-1 is a relevant oncogene whose overexpression or structural changes might play a crucial role in development of human leukemias.

Adult↗
PubMedDate not supplied

[Epstein-Barr, hepatitis B and hepatitis C virus infections and their oncogenic potentials].

There are two ways of connecting Epstein-Barr virus (EBV) with the uncontrolled growth of EBV infected B lymphocytes: in case of evident immunosuppression when the control by cellular immunity is missing or in the case of pathological growth of malignant clone as a result of genetic translocations. Today, EBV is linked with the development of lymphomas in immunosuppressed patients, Hodgkin's and Burkitt's lymphoma and nasopharyngeal carcinoma. The presence of EBV genome in these patients can be confirmed in malignant cells, in lower or higher percent, as well as the high titers of antibodies against specific virus antigens. Hepatitis B viral infection (HBVI) of specific chronic course and associated with intensified inflammation and mitotic activity is of one of the most important factors in the appearance of hepatocellular carcinoma. Although the integration of viral DNA in DNA of hepatocytes has been one of the possible preconditions for carcinogenesis, recently a great attention has been paid to the inactivation of p53 suppressor gene, being a transcriptive transactivator. Other possible cofactors of carcinogenesis imply long-lasting viral replication, coinfection with HVB, HCV or HDV, interaction with other chemical carcinogens (hormones, aflatoxin, alcohol and similar). In distinction from other human DNA viruses, Hepatitis C virus (HCV) is a RNA virus which is not integrated in genome of hepatocyte and active replication of virus is maintained even when hepatocellular carcinoma is detected. It has been assumed that HCV inactivate or mutate the gene of tumor suppression p53 in an early stage of hepatocellular carcinoma development.

Carcinoma, Hepatocellular↗
PubMed1998

Detection of the SYT-SSX chimeric RNA of synovial sarcoma in paraffin-embedded tissue and its application in problematic cases.

We report the development of a reverse-transcriptase polymerase chain reaction assay that detects (in paraffin-embedded, formalin-fixed tissue) the SYT-SSXchimeric RNA transcript resulting from the t(X;18) of synovial sarcoma. The primers chosen detect both of the SSX1 and SSX2 partners, and the target sequence is small enough (87 base pairs) to be reliably detected in archival and variably processed consultation material. To demonstrate its usefulness, we applied it to 14 problematic cases, including spindle cell tumors of the thoracic region, of the neck, and of subcutaneous tissue. For instance, we show that, depending on the location, synovial sarcoma can mimic malignant solitary fibrous tumor, the spindle epithelial tumor with thymus-like differentiation, or skin adnexal tumors. Molecular detection of the SYT-SSX chimeric RNA should allow the reclassification of difficult cases in which the morphologic features overlap different entities or in which tumor nosology is still evolving.

Adult↗
PubMed1998

Role of histone deacetylases in acute leukemia.

Accumulating evidence points to a connection between cancer and transcriptional control by histone acetylation and deacetylation. This is particularly true with regard to the acute leukemias, many of which are caused by fusion proteins that have been created by chromosomal translocations. Genetic rearrangements that disrupt the retinoic acid receptor-alpha and acute myeloid leukemia-1 genes create fusion proteins that block terminal differentiation of hematopoietic cells by repressing transcription. These fusion proteins interact with nuclear hormone co-repressors, which recruit histone deacetylases to promoters to repress transcription. This finding suggests that proteins within the histone deacetylase complexes may be potential targets for pharmaceutical intervention in many leukemia patients.

Acute Disease↗