Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent observations of chimerism in patients relapsed following an allotransplant suggest the persistence of immunotolerance, thus offering a biologic rationale for the use of donor lymphocyte transfusion (DLT). In this study, we have analyzed by PCR amplification of several VNTR regions, sequential bone marrow and peripheral blood DNA samples in four patients who received DLT for CML relapse after bone marrow transplantation. Prior to DLT, all patients showed mixed chimerism in peripheral blood cells while two had mixed chimerism and two no chimerism in the BM. None of these four patients showed evidence of chimerism at the cytogenetic level (all had 100% +ve metaphases). After DLT, a complete hematologic and molecular remission (ie disappearance of the BCR/ABL fusion transcript) was obtained in the two patients who had bone marrow mixed chimerism prior to DLT. The two patients without evidence of marrow chimerism prior to DLT converted to a pattern of mixed chimerism after DLT, but both developed a severe bone marrow aplasia occurring at day 56 and 36, respectively. With regard to the sequential analysis of bone marrow chimerism after DLT we observed that: (1) the disappearance of BCR/ABL +ve cells paralleled the conversion to a pattern of full donor chimerism; and (2) the time interval to achieve CR was inversely correlated with the percentage of donor DNA in bone marrow. In conclusion, we have shown here that the assessment of bone marrow pre-DLT chimerism by PCR analysis might predict the response in patients with favorable characteristics, and also might identify patients at high risk of developing severe myelosuppression.
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PMID:Sequential molecular monitoring of chimerism in chronic myeloid leukemia patients receiving donor lymphocyte transfusion for relapse after bone marrow transplantation. 915 48

The Philadelphia (Ph) chromosome was the first chromosomal abnormality associated with a specific leukemia, chronic myeloid leukemia (CML). This chromosome arises from the t(9;22)(q34;q11) translocation which results in the juxtaposition of the bcr gene and the abl proto-oncogene. This BCR/ABL fusion gene encodes for a hybrid protein with the capacity of oncogenic transformation of hematopoietic cells. Nonetheless, very few myeloproliferative disorders (about 10%) included under the generic term of CML have no Ph chromosome. Half of these Ph-negative CML have the BCR/ABL fusion gene (BCR-positive) and are considered equivalent to Ph-positive CML. In contrast, the patients without detectable BCR/ABL fusion (BCR-negative) fulfil the criteria for atypical CML (aCML) of the French-American-British (FAB) classification, despite considerable variability at the individual level. Due to the very small number of patients with precise cytological descriptions already published, cooperative studies focused on aCML are warranted to draw definitive conclusions and to provide some pointers on physiopathology.
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PMID:Clinical and biological aspects of Philadelphia-negative/BCR-negative chronic myeloid leukemia. 916 33

We describe a method of spectrophotometric detection of BCR/ABL chimeric sequences amplified by multiplex reverse transcriptase-polymerase chain reaction (RT-PCR), enabling the use of archival hematologic slides as RNA sources. Multiplex PCR amplified b3a2, b2a2, and e1a2 break points of the BCR/ABL translocation and the normal ABL gene product. Assessment of sensitivity, performed on K562 cells, showed that the threshold approximated radioactive methods of detection (i.e., 1 positive cell in 1 x 10(6) negative cells for single round PCR and lower than 1 positive cell in 1 x 10(7) negative cells for nested PCR). Then, we assayed 38 different archival hematologic slides from 18 patients, including 11 cases of chronic myelogenous leukemia or chronic myelogenous leukemia-like disease, such as a case of myelofibrosis and a case of chronic neutrophilic leukemia, 6 cases of acute lymphoblastic leukemia, and 1 case of acute myelogenous leukemia. Amplification and spectrophotometric detection of BCR/ABL fusion messenger RNAs gave an unambiguous positive result in 24 (89%) of 27 expected positive slides, among which 17 (63%) were positive after a single PCR round. Concordant unambiguous results were obtained from 35 (92%) of 38 slides, as verified through parallel analyses of corresponding cryopreserved cells. Retrospective analysis on archival hematologic slides yielded identification of the presence or absence of the t(9;22) translocation and break point in 14 previously uncharacterized cases. The application of this method can help define the diagnosis of cases lacking other appropriate material and assist in the retrospective analysis of large patient series for which only smears are available.
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PMID:Spectrophotometric detection of RT-PCR-amplified BCR/ABL fusion transcripts. A survey performed on archival hematologic slides. 932 90

Chronic myelogenous leukemia (CML) is a clonal disorder starting with a chronic phase and progressing to an acute blastic phase. Philadelphia (Ph) chromosome formation results in the relocation of the ABL oncogene from the chromosome 9q34 to BCR region on 22q11, forming the BCR/ABL fusion gene. The Ph chromosome once detected rarely disappears, except as a result of therapy. We present an unusual Ph-positive CML case, which developed lymphoid blast crisis in complete cytogenetic remission following interferon-alpha and hydroxyurea therapy. Sequential cytogenetic investigations were carried out on bone marrow. After a standard Ph translocation seen at diagnosis, from the 8th month of therapy all metaphases showed a normal diploid karyotype. Fluorescence in situ hybridization detected residual BCR/ABL-positive interphase cells during the 12th month of therapy. In the 14th month, the patient showed 27% blasts in marrow though normal cytogenetics was maintained. Present findings suggest blastic transformation occurred in a Ph-negative lymphoid clone. This supports the hypothesis that an actual leukemogenic event occurs in a multipotent stem cell prior to the acquisition of Ph translocation.
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PMID:Lymphoid blast crisis during complete cytogenetic remission following interferon-alpha and hydroxyurea therapy. 935 47

The results of polymerase chain reaction (PCR) analysis after transplantation for chronic myelogenous leukemia (CML) are difficult to interpret clinically. Positive findings for BCR/ABL can be seen not only in patients who go on to relapse but also in patients who, after years of follow-up, remain in complete remission. The cause for the lack of concordance between PCR findings and relapse is not clear. We identified two patients with CML who had rare pseudo-Gaucher cells in their bone marrow aspirate specimens prior to, and at 1, and 6 or 12 months following syngeneic or allogeneic hematopoietic transplantation. After the transplant, the patients obtained clinical remission and were shown to be cytogenetically normal and to have germline MBCR in blood or bone marrow by Southern analysis. One patient was PCR-positive for BCR/ABL in the marrow at 12 months. In order to determine whether the pseudo-Gaucher histiocytes were BCR/ABL-positive, we used fluorescence in situ hybridization and probes for MBCR and ABL and analyzed Wright-stained smears to correlate molecular cytogenetic findings with cell type. On three aspirate smears from each patient (at 6 or 12 months post-transplant), all of the pseudo-Gaucher cells studied (10/10 in one patient and 12/12 in the other) showed the fusion for BCR/ABL. Other cells analyzed randomly (erythroid precursors, granulocytes and rare monocytes, lymphocytes and plasma cells) did not. Our cases provide the first proof that pseudo-Gaucher cells carry the BCR/ABL fusion. Furthermore, they illustrate that these cells can be found in the marrow for up to 12 months following transplantation. Our results permit speculation that pseudo-Gaucher cells or other long-lived histocytes may be one cause of persistent PCR positivity after transplantation that is not predictive of disease relapse.
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PMID:Pseudo-Gaucher histiocytes identified up to 1 year after transplantation for CML are BCR/ABL-positive. 951 87

We investigated a new method using fluorescence in situ hybridization and DNA probes that span the common breakpoints of t(9;22)(q34;q11.2) and that detect double BCR/ABL fusion (D-FISH) in bone marrow cells with this translocation, one on the abnormal chromosome 9 and one on the Philadelphia chromosome (Ph chromosome). D-FISH patterns were abnormal in 30 of 30 specimens with classic, simple, complex, and masked Ph chromosomes. Based on 200 nuclei from each of 30 normal specimens, the mean percentage of false-positive cells was 0.25 +/- 0.39. Thirty-seven specimens from 10 patients were studied before treatment and two or more times at 4-month intervals after treatment with interferon-alpha2b (IFN-alpha2b) with or without ara-C. Based on 200 nuclei, the results of D-FISH in these specimens correlated closely with quantitative cytogenetics and accurately quantified disease within a few percent. We studied 6, 000 nuclei for each of six specimens, three normal and three from patients with chronic myeloid leukemia (CML) in cytogenetic remission. The normal cutoff for 6,000 nuclei was 0.079% and patients in cytogenetic remission had residual disease ranging from 7 (0.117%) to 53 (0.883%) Ph-positive nuclei. We conclude that D-FISH can detect the Ph chromosome and its variant translocations and accurately quantify disease in CML at diagnosis and at all times after treatment, including cytogenetic remission.
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PMID:Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. 955 93

We report cytogenetic, fluorescence in situ hybridization (FISH), and molecular analysis in a case of Ph-negative chronic myelogenous leukemia patient with ABL/BCR fusion gene on chromosome 9 and a disparate FISH signal pattern using two commercially available bcr/abl probes (Vysis, Inc. and Oncor, Inc.). Cytogenetic analysis revealed a 46,XX normal female karyotype. FISH studies using Vysis LSI bcr/abl probe in interphase cells demonstrated a BCR/ABL fusion pattern, similar to that of m-BCR/ABL fusion found in acute lymphoblastic leukemia. However, examination of metaphases revealed the ABL/BCR fusion signal on one of the chromosomes 9, an ABL signal on the other chromosome 9, and two BCR signals of different sizes on each of the chromosomes 22. Subsequently, a FISH study with the Oncor major (M)-bcr/abl translocation probe confirmed the ABL/BCR fusion signal on chromosome 9 in addition to an ABL signal and a BCR signal located on chromosomes 9 and 22, respectively. Molecular studies (RT-PCR) revealed a rearrangement of the M-BCR region and expression of a chimeric bcr/abl mRNA of b3a2 configuration. This case suggests that it is imperative to have a full understanding of both the capabilities and the limitations of bcr/abl translocation probes and that FISH interphase signals should be confirmed on metaphase spreads for accurate diagnosis.
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PMID:The ABL/BCR fusion gene on chromosome 9 in Ph-negative chronic myelogenous leukemia: a case for vigilance in fluorescence in situ hybridization interpretation. 964 60

We used two-color fluorescence in situ hybridization (FISH) to detect BCR/ABL fusion in interphase nuclei in bone marrow of 17 patients with chronic myeloid leukemia (CML) before and in the course of interferon therapy. The results of FISH were compared with the data of conventional cytogenetic investigation (G- or Q-banding) of the same specimens. Changes in percentage of Ph-positive nuclei correlated with variations in percentage of Ph-positive metaphases. An overall difference in the classification of patients by conventional cytogenetics and FISH based on the percentage of Ph-positive cells was not observed. This FISH method is reproducible, relatively easy to perform, and reliable for monitoring patients with CML.
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PMID:Fluorescence in situ hybridization studies of interphase nuclei for assessing response to therapy in patients with chronic myeloid leukemia. 979 77

A 40-year-old man had chronic myeloid leukemia (CML) and an apparently normal karyotype. Fluorescence in situ hybridization with a BCR/ABL1-S probe, which is formatted to display a BCR/ABL fusion signal on chromosome 22, gave a positive fusion signal on a chromosome 9. Therefore this patient has a BCR/ABL fusion gene on chromosome 9. The BCR/ABL1-D probe, formatted to display a fluorescent signal for both the reciprocal products of a 9/22 rearrangement, gave a positive fusion signal on the derivatives 9 and 22. These findings favor either a cryptic reciprocal exchange between BCR and ABL loci or the reversal of a Philadelphia translocation. An insertion of BCR next to ABL is ruled out. The reverse-transcriptase polymerase chain reaction provided molecular evidence that a typical CML chimeric product resulting from a fusion of BCR exon 2 with C-ABL exon II, a2b2, is present.
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PMID:A Philadelphia-negative chronic myeloid leukemia with a BCR/ABL fusion gene on chromosome 9. 980 34

We examined the effect of norsegoline, a natural marine product, and dibezine, a synthetic product, on the survival of human myeloid progenitor cells [colony-forming unit-cells (CFU-C)] from normal individuals and from 10 patients with Philadelphia-positive chronic myelogenous leukemia (CML) in chronic phase and blastic crisis. We compared their effect to the effect of IFN-alpha. Norsegoline, dibezine, and IFN-alpha inhibited the proliferation of CFU-C in a dose-dependent manner. The number of CFU-C from bone marrow (BM) of five CML patients in chronic phase exposed for 16 h to norsegoline (10(-8)-10(-6)M), dibezine (10(-8)-10(-6)M), and IFN-alpha (500 units/ml) was found to be statistically lower (P < 0.05) than the number of CFU-C derived from normal individuals. A 16-h drug exposure of CD34(+) cells isolated from the peripheral blood of three CML patients in blastic crisis and from BM of two patients in chronic phase resulted in a marked inhibition in the ability of the cells to proliferate in liquid culture and a reduction in CFU-C content. Using the fluorescent in situ hybridization technique, we evaluated detection of the BCR/ABL fusion product in the CD34(+) cells. All five patients were 100% Philadelphia positive at diagnosis. BCR/ABL translocations were detected in 94.6 +/- 0.6% of cells following their growth in liquid culture for 7 days. Following exposure of CD34(+) cells to norsegoline, dibezine, or IFN-alpha, BCR/ABL fusion signals could be detected in 73 +/- 11%, 66.5 +/- 4. 7%, and 66.0 +/- 2.5% of cells from BM and 72.3 +/- 5%, 68.8 +/- 7%, and 60.6 +/- 6.8% of peripheral blood, respectively. Our data indicate that norsegoline and dibezine have in vitro an antileukemic effect against Philadelphia-positive cells and may be used in conjunction with currently available agents for ex vivo purging of BM and/or peripheral blood of CML patients in conjunction with autologous bone marrow transplantation.
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PMID:Potent antileukemic activity of the novel agents norsegoline and dibezine. 981 51


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