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)

We investigated an intensified conditioning regimen including fractionated total body irradiation (12 Gy), etoposide (30-45 mg/kg) and cyclophosphamide (120 mg/kg), followed by autologous (n = 5), allo-related (n = 13) or allo-unrelated (n = 6) bone marrow (n = 22) or peripheral stem cell (n = 2) transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. One patient received busulfan (16 mg/kg) instead of TBI. Nineteen patients were transplanted in 1CR, two in 2CR, one in 1PR and two in relapse. Major toxicity was mucositis grade II according to the Bearman scale in all patients. The treatment-related mortality was 25%, mainly due to infection or GVHD after allogeneic transplantation. After a median follow-up of 45 months (range 2-93), nine patients (37.5%) remain alive in CR. Nine patients (37.5%) relapsed and eight (33.3%) of these subsequently died. After autologous transplantation, four of five patients (80%) relapsed and died. Late relapse was seen after allogeneic, as well as autologous transplantation, at 33 and 59 months, respectively. The Kaplan-Meier estimate of leukemia-free survival for all patients is 38% at 3 years (95% CI: 18-58%) and 35% at 5 years (95% CI: 15-55%). For allogeneic transplants in first CR (n = 15) the estimate of disease-free survival was 46% at 3 years (95% CI: 19-73%) and 34% at 5 years (95% CI: 17-51%). Patients aged below 30 years had a better estimated overall survival at 3 years (61% vs 11%, P < 0.001). The bcr-abl fusion transcript (p210 vs p190 vs p210/190) did not affect disease-free or overall survival. In our experience, an intensified conditioning regimen seems to improve the results of bone marrow transplantation in patients with Ph+ acute lymphoblastic leukemia. However, the high relapse rate warrants novel approaches to enhance anti-leukemic efficacy.
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PMID:Intensified conditioning regimen in bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. 987 63

Myeloperoxidase (MPO) is found in the azurophilic granules of normal myelocytic cells. Cytochemical staining for MPO activity is used clinically to distinguish myeloid from acute lymphoid leukemias (ALL). However, using a highly sensitive RT-PCR technique, it is possible to detect MPO mRNA in otherwise clear ALL. The significance of this finding remains poorly understood. We have extended our observations to a series of 57 patients with the primary diagnosis of ALL (46 patients tested at diagnosis and 11 cases at relapse). We identified 25 cases (43.8%) of MPO mRNA(+)/enzyme(-) ALL (17 B cell and eight T cell lineage). Expression of myeloid antigens (CD13 or CD33) were detected in nine of them, and remarkably, 18 cases (72%) displayed CD34. Of these 25 MPO mRNA(+) leukemias, 10 (40%) are Bcr-Abl positive (with P210 fusion transcript in five patients while the five remaining cases carried P190 transcript). Moreover, 11 of 16 myeloid negative cases were also negative for any type of Bcr-Abl and MLL rearrangement, indicating that MPO mRNA positivity is not either invariably related to that chromosomal abnormality or necessarily associated with the presence of other myeloid differentiation features. Interestingly, six of these 11 cases are T-ALL, suggesting the presence of some overlapping phase for T and myeloid lineage commitment. Taken together, these findings could suggest a separate biological disease with immature origin and bipotential differentiation capability, which involves B and T-ALL subtypes and should lead to new investigations regarding their prognostic impact.
Leukemia 1999 Feb
PMID:Genetic, phenotypic and clinical features of acute lymphoblastic leukemias expressing myeloperoxidase mRNA detected by RT-PCR. 1158 32

We describe a one-tube multiplex reverse transcription polymerase chain reaction (RT-PCR) assay for the detection of bcr-abl fusion mRNA in analysis of patients with chronic myeloid leukaemia and acute lymphoblastic leukaemia. The assay provides a quick and reliable method for the detection and analysis of chromosome translocations resulting in formation of the fusion proteins p210 (b3a2/b2a2) and p190 (e1a2). The method is based on the use of magnetic beads and sequence-specific reverse transcription primers. By combining direct mRNA isolation, reverse transcription and first-stage PCR we have reduced the number of manipulations, maintained sensitivity, and minimized the risk of contamination. A nested primer strategy is used to secure sensitivity. We also introduce a competitive one-tube RT-PCR to be able to monitor the relative quantity of transcripts using in vitro transcribed RNA as competitor.
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PMID:One-tube multiplex RT-PCR of BCR-ABL transcripts in analysis of patients with chronic myeloid leukaemia and acute lymphoblastic leukaemia. 1008 1

The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists in three principal forms (P190, P210, and P230 BCR/ABL) that are found in distinct forms of Ph-positive leukemia, suggesting the three proteins have different leukemogenic activity. We have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vivo leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Although all three oncogenes transformed both myeloid (32D cl3) and lymphoid (Ba/F3) interleukin (IL)-3-dependent cell lines to become independent of IL-3 for survival and growth, their ability to stimulate proliferation of Ba/F3 lymphoid cells differed and correlated directly with tyrosine kinase activity. In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)-like myeloproliferative syndrome in recipient mice when 5-fluorouracil (5-FU)-treated donors were used. Analysis of proviral integration showed the CML-like disease to be polyclonal and to involve multiple myeloid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gave rise to day 12 spleen colonies and induced disease in secondary recipients, suggesting heterogeneity among the target cell population. In contrast, when marrow from non- 5-FU-treated donors was used, a mixture of CML-like disease, B lymphoid acute leukemia, and macrophage tumors was observed in recipients. P190 BCR/ABL induced lymphoid leukemia with shorter latency than P210 or P230. The lymphoid leukemias and macrophage tumors had provirus integration patterns that were oligo- or monoclonal and limited to the tumor cells, suggesting a lineage-restricted target cell with a requirement for additional events in addition to BCR/ABL transduction for full malignant transformation. These results do not support the hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans, and suggest that the rarity of P190 BCR/ABL in human CML may reflect infrequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210.
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PMID:The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. 1022 80

We analysed 20 patients with BCR-ABL-positive acute lymphoblastic leukaemia (ALL) by quantitative competitive polymerase chain reaction (QC-PCR) to study the kinetics of the leukaemic clone. Consecutive samples of 16 patients (minor-bcr, n = 10; major-bcr, n = 6) were analysed after conventional chemotherapy and/or bone marrow transplantation (BMT). DNA competitor templates co-amplifying with either p210 or p190 BCR-ABL cDNA were used for quantification of leukaemia-specific BCR-ABL mRNA. In all samples, total ABL transcripts were measured as internal control, and the percentage of BCR-ABL/ABL molecules was calculated. Following induction chemotherapy the number of BCR-ABL transcripts was reduced by a maximum of 2-3 logs. In most patients, additional chemotherapy did not lead to further reduction of BCR-ABL mRNA. In two patients, conventional chemotherapy plus autologous BMT in complete haematological remission resulted in a total reduction of the transcript level of more than 3 logs. In two other patients, allogeneic BMT caused a transient reduction of the BCR-ABL transcripts below the detection level of our method (<1 blast cell in 105 normal cells) for a period of 7 and 11 months, respectively. The achievement of PCR negativity did not guarantee sustained remission. Both patients relapsed and BCR-ABL transcript levels rose by more than 1 log prior to frank relapse. Our data demonstrate that quantification of BCR-ABL mRNA allows the evaluation of the dynamics of the leukaemic clone and thus is valuable for the evaluation of minimal residual leukaemia following various therapies and the early detection of increasing BCR-ABL transcripts prior to relapse.
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PMID:Quantification of minimal residual disease in patients with BCR-ABL-positive acute lymphoblastic leukaemia using quantitative competitive polymerase chain reaction. 1046 51

The Philadelphia chromosome is present in a heterogeneous group of leukemias. It is most commonly associated with chronic myelogenous leukemia (CML) and B-lineage acute lymphoblastic leukemia (ALL) being found in more than 95% and 15-25% of cases respectively. We undertook a study to determine the morphologic, phenotypic and molecular diversity of Philadelphia positive de novo acute leukemia patients seen at our institution over the past 3 1/2 years. Twenty-one patients with de novo acute leukemia were found to have the Philadelphia chromosome by cytogenetic studies. They consisted of 3 patients with acute myelogenous leukemia (AML), 1 biphenotypic leukemia and 17 ALL patients. Of the patients with ALL, 16 were of B-lineage while 1 had a T-cell phenotype. Ten patients expressed the p210 BCR-ABL transcript alone and 10 expressed only the p190 BCR-ABL transcript. One patient had co-expression of p190 and p210 b3a2 BCR-ABL transcripts. Thus the Philadelphia chromosome can be found in a diverse cohort of morphologic and immunologic subtypes of de novo acute leukemia reflecting the heterogeneity of lineage involvement in this disease.
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PMID:Molecular and phenotypic spectrum of de novo Philadelphia positive acute leukemia. 1056 81

Prospective studies on the detection of minimal residual disease (MRD) in acute leukemia patients have shown that large-scale MRD studies are feasible and that clinically relevant MRD-based risk group classification can be achieved and can now be used for designing new treatment protocols. However, multicenter international treatment protocols with MRD-based stratification of treatment need careful standardization and quality control of the MRD techniques. This was the aim of the European BIOMED-1 Concerted Action 'Investigation of minimal residual disease in acute leukemia: international standardization and clinical evaluation' with participants of 14 laboratories in eight European countries (ES, NL, PT, IT, DE, FR, SE and AT). Standardization and quality control was performed for the three main types of MRD techniques, ie flow cytometric immunophenotyping, PCR analysis of antigen receptor genes, and RT-PCR analysis of well-defined chromosomal aberrations. This study focussed on the latter MRD technique. A total of nine well-defined chromosome aberrations with fusion gene transcripts were selected: t(1;19) with E2A-PBX1, t(4;11) with MLL-AF4, t(8;21) with AML1-ETO, t(9;22) with BCR-ABL p190 and BCR-ABL p210, t(12;21) with TEL-AML1, t(15;17) with PML-RARA, inv (16) with CBFB-MYH11, and microdeletion 1p32 with SIL-TAL1. PCR primers were designed according to predefined criteria for single PCR (external primers A <--> B) and nested PCR (internal primers C <--> D) as well as for 'shifted' PCR with a primer upstream (E5' primer) or downstream (E3' primer) of the external A <--> B primers. The 'shifted' E primers were designed for performing an independent PCR together with one of the internal primers for confirmation (or exclusion) of positive results. Various local RT and PCR protocols were compared and subsequently a common protocol was designed, tested and adapted, resulting in a standardized RT-PCR protocol. After initial testing (with adaptations whenever necessary) and approval by two or three laboratories, the primers were tested by all participating laboratories, using 17 cell lines and patient samples as positive controls. This testing included comparison with local protocols and primers as well as sensitivity testing via dilution experiments. The collaborative efforts resulted in standardized primer sets with a minimal target sensitivity of 10-2 for virtually all single PCR analyses, whereas the nested PCR analyses generally reached the minimal target sensitivity of 10-4. The standardized RT-PCR protocol and primer sets can now be used for molecular classification of acute leukemia at diagnosis and for MRD detection during follow-up to evaluate treatment effectiveness.
Leukemia 1999 Dec
PMID:Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. 1060 11

The Philadelphia chromosome translocation t(9;22)(q34;q11) may give rise to different BCR/ABL fusion mRNAs due to different genomic breakpoints and alternative splicing. The e1a2, b2a2 or b3a2 and c3a2 fusion mRNAs encode distinct fusion proteins (p190, p210 and p230, respectively), which are associated with different forms of leukemogenesis in humans and animal models. Our patient presented with acute pre-B cell lymphoblastic leukemia (ALL) with normal cytogenetics. After 3 years of standard ALL therapy, he relapsed with t(9;22)-positive chronic myelogenous leukemia (CML). Retrospective molecular analyses of the pre-treatment pre-B cell ALL sample showed the b3a2 (p210) and e1a2 (p190) BCR/ABL fusion transcripts. Only the b3a2 (p210) transcript was detected at relapse. Southern and immunoglobulin heavy chain (IgH) analyses of the presentation and relapse samples revealed an identical BCR rearrangement in both samples. However, only the ALL sample harbored an IgH gene rearrangement. These findings show a clonal relationship between the more differentiated pre-B cell and less differentiated CML clones and that the p210 and p190 fusion mRNAs were alternatively spliced from a single genomic breakpoint. Our patient's unusual molecular findings provide circumstantial evidence that the p190 protein may promote a more differentiated phenotype in a comparatively less differentiated p210-transformed precursor cell.
Leukemia 1999 Dec
PMID:Pre-B acute lymphoblastic leukemia with b3a2 (p210) and e1a2 (p190) BCR-ABL fusion transcripts relapsing as chronic myelogenous leukemia with a less differentiated b3a2 (p210) clone. 1060 22

Cancer is thought to arise from multiple genetic events that establish irreversible malignancy. A different mechanism might be present in certain leukaemias initiated by a chromosomal translocation. We have taken a new approach to determine if ablation of the genetic abnormality is sufficient for reversion by generating a conditional transgenic model of BCR-ABL1 (also known as BCR-ABL)-induced leukaemia. This oncogene is the result of a reciprocal translocation and is associated with different forms of leukaemia. The most common form, p210 BCR-ABL1, is found in more than 90% of patients with chronic myelogenous leukaemia (CML) and in up to 15% of adult patients with de novoacute lymphoblastic leukaemia (ALL). Efforts to establish a useful transgenic model have been hampered by embryonic lethality when the oncogene is expressed during embryogenesis, by reduced penetrance or by extremely long latency periods. One model uses the 'knock-in' approach to induce leukaemia by p190 BCR-ABL1(ref. 10). Given the limitations of models with p210, we used a different experimental approach. Lethal leukaemia developed within an acceptable time frame in all animals, and complete remission was achieved by suppression of BCR-ABL1expression, even after multiple rounds of induction and reversion. Our results demonstrate that BCR-ABL1is required for both induction and maintenance of leukaemia.
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PMID:Reversibility of acute B-cell leukaemia induced by BCR-ABL1. 1061 28

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABL gene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABL(p190) and BCR-ABL(p210), are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(1)-ALL). In CML, the transformation occurs at the level of pluripotent stem cells. However, Ph(1)-ALL is thought to affect progenitor cells with lymphoid differentiation. Here we demonstrate that the cell capable of initiating human Ph(1)-ALL in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID), termed SCID leukemia-initiating cell (SL-IC), possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all Ph(1)-ALL analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34(+ )CD38(-), which is similar to the cell-surface phenotype of normal SCID-repopulating cells. This indicates that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph(1)-ALL.
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PMID:A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. 1078 38


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