Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-two cases of childhood acute lymphoblastic leukaemia (ALL) with normal G- or Q-banded karyotypes were studied by interphase fluorescence in situ hybridization (FISH) and spectral karyotyping. Probes detecting MLL, BCR/ABL and TEL/AML1 rearrangements were used for the interphase studies, along with centromere-specific probes from chromosomes 17 and X. In 10 patients (45%), previously undetected aberrations were demonstrable. Specific gene rearrangements and structural changes were found in six cases and numerical changes in five. Five of these aberrations have previously been reported to have an impact on prognosis. Three cases were massively hyperdiploid and, in one, the prognostically important BCR/ABL fusion was detected. In addition, a near-haploid karyotype with 27 chromosomes was found in one patient and TEL/AML1 rearrangements were detected in two cases. This study indicates that about half of childhood ALL cases with apparently normal karyotypes harbour genetic aberrations that may be detected using interphase FISH and spectral karyotyping.
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PMID:Interphase fluorescence in situ hybridization and spectral karyotyping reveals hidden genetic aberrations in children with acute lymphoblastic leukaemia and a normal banded karyotype. 1156 64

In acute lymphoblastic leukaemia (ALL) the karyotype provides important prognostic information which is beginning to have an impact on treatment. The most significant structural chromosomal changes include: the poor-risk abnormalities; t(9;22)(q34;q11), giving rise to the BCR/ABL fusion and rearrangements of the MLL gene; abnormalities previously designated as poor-risk; t(1;19)(q23;p13), producing the E2A/PBX1 and rearrangements of MYC with the immunoglobulin genes; and the probable good risk translocation t(12;21)(p13;q22), which results in the ETV6/AML1 fusion. These abnormalities occur most frequently in B-lineage leukaemias, while rearrangements of the T cell receptor genes are associated with T-lineage ALL. Abnormalities of the short arm of chromosome 9, in particular homozygous deletions involving the tumour suppressor gene (TSG) p16(INK4A), are associated with a poor outcome. Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (51-65 chromosomes) is associated with a good risk, whereas the outlook for patients with near haploidy (23-29 chromosomes) is extremely poor. In view of the introduction of risk-adjusted therapy into the UK childhood ALL treatment trials, an interphase FISH screening programme has been developed to reveal chromosomal abnormalities with prognostic significance in childhood ALL. Novel techniques in molecular cytogenetics are identifying new, cryptic abnormalities in small groups of patients which may lead to further improvements in future treatment protocols.
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PMID:Acute lymphoblastic leukaemia. 1164 Aug 71

A 56-year-old male presented with inguinal lymphadenopathy and leucocytosis (WBC 98 x 10(9)/l). Bone marrow morphology showed myeloid hyperplasia, with eosinophilia. Cytogenetic analysis showed no evidence of the Philadelphia chromosome, and fluorescence in situ hybridisation studies for the BCR/ABL fusion were negative. All cells examined showed the t(8;13)(p11;q12) translocation. Six weeks after presentation, the disease progressed to an acute lymphoblastic leukaemia (ALL). The lymphoblasts were CD19/CD10 dual positive. Cytogenetic analysis again showed the t(8;13) translocation, with no additional abnormalities. There have been at least 14 reported cases of the t(8;13) myeloproliferative disorder to date, of which only 3 transformed to B-lineage ALL: our case is the 4th.
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PMID:A fourth case of 8p11 myeloproliferative disorder transforming to B-lineage acute lymphoblastic leukaemia. A case report. 1191 90

A 17-year-old Japanese woman with Ewing's sarcoma was initially treated with conventional chemotherapy and local irradiation, and then with high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation. Four years later she was diagnosed with chronic myelogenous leukaemia (CML). The BCR/ABL fusion gene was detected in both peripheral blood and bone marrow cells by reverse transcription-polymerase chain reaction, but not in the harvest product of peripheral blood stem cells which were infused at the time of transplantation. This case adds to the accumulating evidence of therapy-related CML developing after high-dose chemotherapy and autologous stem cell transplantation.
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PMID:Therapy-related chronic myelogenous leukaemia following autologous stem cell transplantation for Ewing's sarcoma. 1202 29

BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph(1))-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). STI571 (Gleevec), a novel anti-leukemia drug targeting BCR/ABL kinase can induce remissions of the Ph(1)-positive leukemias. STI571 was recently combined with the standard cytostatic drugs to achieve better therapeutic results and to overcome emerging drug resistance mechanisms. We decided to search for a more specific partner compound for STI571. Our previous studies showed that a signaling protein phosphatidylinositol-3 kinase (PI-3k) is essential for the growth of CML cells, but not of normal hematopoietic cells (Blood, 86:726,1995). Therefore the anti- Ph(1)-leukemia effect of the combination of BCR/ABL kinase inhibitor STI571 and PI-3k inhibitor wortmannin (WT) or LY294002 (LY) was tested. We showed that STI571+WT exerted a synergistic effect against the Ph(1)-positive cell lines, but did not affect the growth of Ph(1)-negative cell line. Moreover, the combinations of STI571+WT or STI571+LY were effective in the inhibition of clonogenic growth of CML-chronic phase and CML-blast crisis patient cells, while sparing normal bone marrow cells. Single colony RT-PCR assay showed that colonies arising from the mixture of CML cells and normal bone marrow cells after treatment with STI571+WT were selectively depleted of BCR/ABL-positive cells. Biochemical analysis of the CML cells after the treatment revealed that combination of STI571+WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to STI571 and WT alone. In conclusion, combination of STI571+WT or STI571+LY may represent a novel approach against the Ph(1)-positive leukemias.
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PMID:Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. 1218 86

Children with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) represent a subgroup at very high risk for treatment failure, despite intensive chemotherapy. However, recent retrospective studies showed that Ph+ childhood ALL is a heterogeneous disease with regard to treatment response. We have prospectively monitored, by reverse transcription polymerase chain reaction (RT-PCR) during follow-up, the presence of the BCR/ABL fusion transcript in Ph+ ALL children diagnosed in the Italian multicentre Associazione Italiana Ematologia Oncologia Pediatrica ALL-AIEOP-95 therapy protocol. To our knowledge, this is the first report on the evaluation of minimal residual disease (MRD) in childhood Ph+ ALL prospectively enrolled in an intensive, Berlin-Frankfurt-Munster (BFM)-type treatment protocol. Twenty-seven of 36 (75.0%) Ph+ patients consecutively enrolled into the high-risk group of the AIEOP-ALL protocol between May 1995 and October 1999 were successfully analysed. Twenty were good responders to the pre-phase of prednisone/intrathecal methotrexate treatment (PGR) and seven were poor responders (PPR). Within the PPR group, the RT-PCR monitoring constantly showed positivity for the BCR/ABL fusion transcript and all the patients died of disease progression. In contrast, highly sensitive qualitative RT-PCR monitoring revealed heterogeneity within the PGR group of Ph+ childhood ALL patients. Three different subgroups could be defined, according to the clearance of Ph+ cells within the first 5 months of treatment. This provides useful information on the capability of chemotherapy to reduce the leukaemic clone, with prognostic implications.
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PMID:Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response. 1240 84

The past decade has brought new technologies to the study of minimal residual disease (MRD) in leukemia. Each of them has limitations and is far from being accurate. Recently, a new multiparametric cell scanning system (Duet) was introduced to the field of MRD detection. This system has the advantage of automatically scanning large numbers of cells and performing combined analysis of morphology and fluorescence in situ hybridization (FISH) on the same cell. We used this system to characterize the lineage and degree of maturation of the cells carrying the minor m-BCR/ABL fusion, in a follow-up of an 8-year-old boy with Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL). The boy was treated using a high-risk protocol and was closely monitored with FISH analysis for cells carrying the m-BCR/ABL fusion. Consecutive analysis along 2.5 years from remission showed 0.2-4.5% m-BCR/ALB(+) cells in the peripheral blood (PB), which is within the accepted background range for this method. The combined analysis found that all the m-BCR/ABL(+) cells were mature lymphocytes. Because mature lymphocytes have a long life span in the circulation, this finding supports the fact that the patient is in remission. Moreover, since mature differentiated cells have a low proliferative capacity, there is a low risk for relapse.
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PMID:Combined analysis of morphology and fluorescence in situ hybridization in follow-up of minimal residual disease in a child with Philadelphia-positive acute lymphoblastic leukemia. 1241 87

Conventional cytogenetic analysis (CCA) is the standard method for monitoring of the Philadelphia (Ph) chromosome in chronic myeloid leukemia (CML). Evaluation of breakpoint cluster region/abelson murine leukemia (BCR/ABL) fusion using interphase fluorescence in situ hybridization on peripheral blood smears (PB-FISH) might be another approach allowing more frequent and less invasive follow-up investigations. Herein, BCR/ABL fusion gene was assessed on 21 PB smears from 16 CML patients in chronic phase. Results of PB-FISH were compared with those of CCA and interphase FISH on bone marrow aspirates (BM-FISH). PB-FISH analysis was combined with CD3 immunophenotyping that allowed simultaneous investigation of the leukemic status of CD3(+) T lymphocytes and scoring CD3(-) cells for BCR/ABL fusion gene. Moreover, the frequency of BCR/ABL fusion in nonlymphoid PB cells was estimated according to the differential leukocyte counts. The incidence of BCR/ABL(+) fusion signals in CD3(+) T cells of CML patients was 5.3% (SD +/- 1.9) and did not exceed the normal cut-off value of 8%. A significant correlation (P < 0.001) was found between results of PB-FISH and methods of BM analysis (CCA or BM-FISH). Correction of PB-FISH results to include only nonlymphoid or CD3(-) cells reduced the mean of differences and improved agreement between PB-FISH and CCA or BM-FISH methods. The best agreement was noted between CCA and PB-FISH on nonlymphoid cells. On the other hand, results of BM-FISH agreed well with those of PB-FISH on CD3(-) cells. These findings imply that PB-FISH on nonlymphoid or CD3(-) cells is reliable and may replace BM analysis for monitoring of response to treatment in CML patients.
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PMID:Efficiency of interphase fluorescence in situ hybridization for BCR/ABL on peripheral blood smears for monitoring of CML patients: a comparison with bone marrow findings. 1245 17

We present a patient with a Philadelphia chromosome positive (Ph+) acute lymphocytic leukaemia (ALL) refractory to standard induction chemotherapy. Treatment with the ABL-specific tyrosine kinase inhibitor STI571 (Glivec, Gleevec, imatinib mesylate) resulted in a complete haematologic and cytogenetic remission. Allogeneic stem cell transplantation from an unrelated donor could be undertaken while the patient was in STI571-induced complete remission from the leukaemia. At present, the patient has a 15-month post-transplantation follow-up and is in stable molecular remission as evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for the BCR/ABL fusion gene transcript. Our case demonstrates that STI571 can act as a bridge to potentially curative allogeneic stem cell transplant in otherwise poor prognosis Ph+ ALL.
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PMID:Favorable outcome with STI571 (imatinib mesylate) and allogeneic stem cell transplantation in a case of Ph+ chemorefractory acute lymphocytic leukaemia. 1247 93

To investigate the value of metaphase-fluorescence in situ hybridization (M-FISH) in the diagnosis of acute promyelocytic leukemia (APL) and the detection of its minimal residual disease (MRD), 10 cases of untreated acute myeloid leukemia (AML) (de novo APL 5 cases, relapsed APL 3 cases, AML-M(1) and AML-M(5) one case each) diagnosis by cell morphology at presentation and 10 cases of APL after complete remission (CR) were studied by M-FISH using a whole chromosome 17 painting probe labeled by digoxigenin and the results were compared with that of conventional cytogenetic examination and reverse transcription-polymerase chain reaction (RT-PCR). Among 10 untreated AML cases, 7 had positive M-FISH results, of whom 4 had t (15;17) translocation, 3 had normal karyotype. Six of them had PML/RARalpha fusion transcript except one, in whom RT-PCR did not be performed; 3 had negative M-FISH results, of whom one had del (2q) x 2 abnormalities, who was RT-PCR-positive for PML/RARalpha fusion transcript; one had complex karyotype abnormalities, whose RT-PCR was negative for PML/RARalpha fusion transcript; one had t (9;22) translocation, whose RT-PCR was negative for PML/RARalpha fusion transcript, but positive for BCR/ABL fusion transcript. Thus the diagnosis of AML-M(3) was revised as AML-M(2) for the latter two cases. 10 APL cases after CR had normal karyotype, but 12/15 M-FISH assays detected 1 - 5 t (15;17) positive cells in 9 of them. This finding is compatible with the results of RT-PCR assays. Leukemia relapse was seen in one case, and two positive M-FISH results were appeared in the 2 assays at a 13 months' interval. This study suggests that M-FISH had important practical value in the diagnosis of APL and the detection of MRD, and that it is less sensitive than RT-PCR, however, it seems to be more potential for prediction of the relapse of leukemia due to its capacity of detecting quantitatively the chromosome translocation in proliferative cells.
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PMID:[Application of Metaphase-Fluorescence in Situ Hybridization to the Diagnosis of Acute Promyelocytic Leukemia and the Detection of Minimal Residual Disease] 1257 78


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