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Results for “Chromosome Positioning”

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PubMed1999

Leukemia cell lines: in vitro models for the study of Philadelphia chromosome-positive leukemia.

The Philadelphia (Ph) chromosome, the main product of the (9;22)(q34;q11) translocation, is the cytogenetic hallmark of chronic myeloid leukemia (CML), a clonal myeloproliferative disorder of the hematopoietic stem cell; the Ph chromosome is also found in a sizeable portion of acute lymphoblastic leukemia (ALL) patients and in a small number of acute myeloid leukemia (AML) cases. At the molecular level, the t(9;22) leads to the fusion of the BCR gene (on chromosome 22) to the ABL gene (translocated from chromosome 9); this fusion gene BCR-ABL with its elevated tyrosine kinase activity must to be central to the pathogenesis of these disorders. Three different breakpoint cluster regions are discerned within the BCR gene on chromosome 22: M-bcr, m-bcr, and mu-bcr. Ph + leukemia cell lines are important tools in this research area. More than 20 ALL-and more than 40 CML-derived Ph + leukemia cell lines have been described. Furthermore, three Ph + B-lymphoblastoid cell lines, established from patients with Ph + ALL or CML, are available. Molecular analysis has documented BCR-ABL fusion genes in three apparently Ph chromosome-negative cell lines, all three derived from CML. Nearly all Ph + ALL cell lines have the m-bcr e1-a2 fusion gene (only two ALL cell lines have a b3-a2 fusion) whereas all CML cell lines, but one carry the M-bcr b2-a2, b3-a2 or both hybrids. The mu-bcr e19-a2 has been detected in one CML cell line. Four cell lines display a three-way translocation involving chromosomes 9, 22 and a third chromosome. Additional Ph chromosomes (up to five) have been found in four Ph + ALL cell lines and in 18 CML cell lines; though in some cell lines the extra Ph chromosome(s) might be caused by the polyploidy (tri- and tetraploidy) of the cells. Another modus to acquire additional copies of the BCR-ABL fusion gene is the formation of tandem repeats of the BCR-ABL hybrid as seen in CML cell line K-562. Both mechanisms, selective multiplication of the der(22) chromosome and tandem replication of the fusion gene BCR-ABL, presumably lead to enhanced levels of the fusion protein and its tyrosine kinase activity (genetic dosage effect). The availability of a panel of Ph + cell lines as highly informative leukemia models offers the unique opportunity to analyze the pathobiology of these malignancies and the role of the Ph chromosome in leukemogenesis.

Adult↗

PubMed1986

Monoclonal antibody study of Philadelphia chromosome-positive blastic leukemias using the alkaline phosphatase anti-alkaline phosphatase (APAAP) technic.

The leukemic cells from 15 cases of Philadelphia chromosome-positive blastic leukemia were immunophenotyped by the alkaline phosphatase anti-alkaline phosphatase (APAAP) immunocytochemical technic using nine monoclonal antibodies (MoAb) reactive with various myeloid or lymphoid antigens. On the basis of morphology, cytochemistry, terminal deoxynucleotidyl transferase (TdT) reactivity, and electron microscopy, five of the cases had been classified as lymphoid; eight, myeloid; one, mixed myeloid-lymphoid; and one, undifferentiated. The blasts from all five lymphoid cases were reactive with lymphocyte differentiation antigen MoAb, and four of five reacted with MoAb to anti-common acute lymphoblastic leukemia-associated antigen (CALLA) (BA3). The blasts from all eight myeloid cases were reactive with MY7, a marker of myelomonocytic differentiation. Some of the blasts from three of the eight myeloid cases reacted with HP1-1D and AP3, markers of megakaryocytic differentiation; megakaryocyte differentiation was confirmed by electron microscopy. In the case classified as mixed myeloid-lymphoid, the blasts showed morphologic and immunophenotypic heterogeneity; ultrastructural studies demonstrated lymphoid, basophil, and erythroid differentiation. The blasts from the case classified as undifferentiated were immunophenotypically heterogeneous. In all cases in which the leukemic cells were also immunophenotyped by flow cytometry, the results correlated well with those obtained by the APAAP technic. The APAAP technic is a reliable method for immunophenotyping leukemias. Advantages of this method include its applicability to routinely prepared blood and bone marrow smears and cytocentrifuge preparations, lack of endogenous peroxidase background staining, and a permanent record.

Adult↗

PubMed2001

Are occupational, hobby, or lifestyle exposures associated with Philadelphia chromosome positive chronic myeloid leukaemia?

OBJECTIVES: To investigate a broad range of occupational, hobby, and lifestyle exposures, suggested as risk factors for Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML). METHODS: A case-control study, comprising 255 Ph+CML patients from southern Sweden and matched controls, was conducted. Individual data on work tasks, hobbies, and lifestyle exposures were obtained by telephone interviews. Occupational hygienists assessed occupational and hobby exposures for each subject individually. Also, occupational titles were obtained from national registries, and group level exposure-that is, the exposure proportion for each occupational title-was assessed with a job exposure matrix. The effects of 11 exposures using individual data and two exposures using group data (organic solvents and animal dust) were estimated. RESULTS: For the individual data on organic solvents, an effect was found for moderate or high intensity of exposure (odds ratio (OR) 3.4, 95% confidence interval (95% CI) 1.1 to 11) and for long duration (15-20 years) of exposure (OR 2.1, 95% CI 1.1 to 4.0). By contrast, the group data showed no association (OR 0.69, 95% CI 0.27 to 1.8; moderate or high intensity versus no exposure). For extremely low frequency electromagnetic fields (EMFs), only individual data were available. An association with long occupational exposure to EMFs was found (OR 2.3, 95% CI 1.2 to 4.5). However, no effect of EMF intensity was indicated. No significant effects of benzene, gasoline or diesel, or tobacco smoking were found. OR estimates below unity were suggested for personal use of hair dye and for agricultural exposures. CONCLUSIONS: Associations between exposure to organic solvents and EMFs, and Ph+CML were indicated but were not entirely consistent.

Adult↗

PubMed1996

Multivariate analysis of prognostic factors in Philadelphia chromosome positive chronic myeloid leukemia: an update of the first series in Thailand.

The prognostic importance of pretreatment clinical and laboratory features was investigated in a group of 243 patients with Philadelphia chromosome positive chronic phase chronic myeloid leukemia from 1977-1995. Chemotherapy consisted of busulfan before 1993 or hydroxyurea after 1993. The overall median survival from diagnosis was 28 months. The mean age of the patients was 38 years, about 10 years below that of Western populations. Univariate analysis identified 4 poor prognostic features: thrombocytopenia, more than 5% peripheral blasts, more than 5% erythroid precursors and less than 7 g/dl of hemoglobin. The median survival times of patients with these 4 risk factors were 5, 11, 11 and 12 months respectively. Multivariate analysis only identified 2 significant prognostic features: thrombocytopenia and more than 5% peripheral blasts. Splenomegaly of more than 10 cm, basophilia and leukocytosis were associated with a shorter median survival but was not statistically significant. A risk scoring system was developed and used to classify patients into low, intermediate and high risk groups at 30.9%, 30.2% and 38.8% respectively. The median survival time according to the low, intermediate and high risk group was observed at 60, 27 and 14 months respectively. Prognostic factors for Thai patients with chronic myeloid leukemia have both similarities and differences with previously observed factors but the median patient survival time is shorter.

Adolescent↗

PubMed1993

Ph1-chromosome positive acute lymphoblastic leukemia: is t(9;22) the initial abnormality?

We report a case of pre-B-cell acute lymphoblastic leukemia (ALL) with the Ph1-chromosome, t(9;22) translocation and P190 associated BCR/ABL rearrangement. One cell with the Ph1-chromosome and t(9;22) also had del(5q). Interestingly, another diploid cell with iso(17q) lacked the Ph1-chromosome and t(9;22). This finding, similar to one reported in chronic myelogenous leukemia, is consistent with the possibility that abnormality manifest as chromosome instability antedates the Ph1-chromosome and t(9;22) in some cases of Ph1-chromosome positive acute leukemia.

Chromosome Aberrations↗

PubMed2000

Silent Philadelphia chromosome: a distinct developmental stage in a philadelphia chromosome-positive chronic myeloproliferation?

In this paper, a patient is described who presented with peripheral blood and bone marrow features uncharacteristic of chronic granulocytic leukemia, which proved to be Philadelphia (Ph) chromosome-positive by metaphase and interphase cytogenetic analyses but lacked the p210 type of BCR/ABL fusion gene mRNA product by two different sensitive RT-PCR assays. In the course of the 32-month follow-up with a termination into a myeloblastic crisis, molecular investigations were performed four times. They indicated a constantly high rate of Ph positive cells and lack of BCR/ABL mRNA expression, except in the second investigation, when the patient showed reverse transcription polymerase chain reaction positivity with b3/a2 type of chimera, fusion gene mRNA expression, and a striking change in the bone marrow histology. Our findings might indicate that the dormant Ph chromosome state may exist not only at the primitive progenitor, but also at the entire peripheral blood cell compartment level.

Base Sequence↗

PubMed1994

[Detection on BCR-ABL fusion gene in Ph1 chromosome positive leukemia by "nested" retrotranscriptase/polymerase chain reaction].

By using "nested" retrotranscriptase/polymerase chain reaction (RT/PCR) technique, we determined the expression patterns of the BCR-ABL fusion gene resulting from the chromosomal translocation t (9; 22) in leukemias with Ph1 chromosome. Three distinct isoforms of fusion gene transcripts were discovered: ela2, b2a2 and b3a2. In 10 cases of chronic myelogenous leukemia (CML), only two types (b2a2 and b3a2) were observed. However, in 8 cases of Ph1 chromosome positive acute lymphoblastic leukemia (Ph1 + ALL), all three types were detected, including two cases characterized by the coexistence of ela2 and b2a2 or b3a2 types. Moreover, the RT/PCR procedure established in the present study proved to be a very sensitive method, allowing the detection of one leukemic cell among 10(5)-10(6) normal cells. Thus, a positive RT/PCR result was obtained in two Ph1 + ALL cases just after chemotherapy-induced clinical remission (CR), suggesting the presence of residual disease. One case remained RT/PCR positive four months after achieving CR and relapsed in the fifth month, while the other case converted to RT/PCR negative eight months later and is now in CR for 18 months. Therefore the detection of BCR-ABL fusion gene is of importance not only in the study of the pathogenesis of Ph1 + leukemias but also in their diagnosis and monitoring of minimal residual disease during CR.

Adolescent↗

PubMed2001

Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13.

BACKGROUND: The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) is generally poor and reports from large studies are scarce. We evaluated the efficacy of allogeneic bone marrow transplantation (allo-BMT) for children with this type of leukemia. PROCEDURE: The chemotherapy regimens consisted of an induction phase and very intensive consolidation followed by a reinduction phase and late intensification treatment. The selection of treatment modalities such as chemotherapy, allo-BMT, or autologous transplantation was made by each institute. The principal endpoint was the outcome of children with Ph(+) ALL according to the treatment options. RESULTS: Thirty-two patients (4.3%) were diagnosed as Ph(+) ALL out of the 741 cases of ALL consecutively enrolled in two protocols of the Tokyo Children's Cancer Study Group (TCCSG) from 1989 to 1994. Thirty patients (93.8%) were induced into complete remission (CR). Of these 30 patients, eight children electively received allo-BMT in the first CR. Six of these patients are in continuous remission at a median follow-up of 58 (range 48-105) months after the diagnosis. One patient died following recurrence and another patient died of graft vs. host disease. Three patients treated with autologous BMT or peripheral blood stem cell transplantation in the first CR experienced a subsequent relapse. In the remaining 19 patients, 13 patients were treated with very high-risk chemotherapy alone and all relapsed within 28 months. One patient was excluded from the analysis because he was treated with standard-risk chemotherapy until relapse. The other five patients were also excluded from the analysis because Philadelphia chromosome was not detected until they relapsed. None of the relapsed patients survived in spite of treatment including allo-BMT. In multivariate analysis, only allo-BMT remained as an independent factor for good prognosis. CONCLUSIONS: The only way to cure children with Ph(+) ALL was allo-BMT in this study and its outcome seemed promising.

Adolescent↗

PubMed2004

Twenty years' experience in allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in the Nagoya Blood and Marrow Transplantation Group.

Between October 1981 and December 2000, 46 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) underwent allogeneic hematopoietic stem cell transplantation (HSCT) in the Nagoya Blood and Marrow Transplantation Group. The median age was 28.5 years (range, 4-51 years). All but one patient achieved engraftment. Grade II-to-IV acute graft-versus-host disease (GVHD) developed in 32.5% of patients, and chronic GVHD developed in 40.5%. The incidences of relapse and treatment-related mortality (TRM) at 5 years were 65% and 26%, respectively. The estimated overall survival rate at 5 years was 23%. Univariate analysis showed that improved disease-free survival (DFS) was independently associated with complete remission (CR) at transplantation (39%), compared with non-CR (8%) (P = .023). Non-CR at transplantation was associated with a higher risk of relapse. Donor type, acute GVHD, and time from diagnosis to HSCT all had a significant effect on TRM. In a multivariate analysis, 9 months or more from diagnosis to HSCT was the only variable statistically significant for DFS (relative risk, 3.22; P = .01). This study demonstrates that allogeneic HSCT cures a significant population of patients with Ph+ ALL. Relapse is the major obstacle limiting the success of HSCT. Early transplantation during CR from donors, including unrelated persons or mismatched relatives, may offer improved long-term DFS.

Adolescent↗

PubMed1988

Cytogenetic follow-up of 100 patients submitted to bone marrow transplantation for Philadelphia chromosome-positive chronic myeloid leukemia. Cooperative Study Group on Chromosomes in Transplanted Patients.

100 Ph+ CML patients submitted to BMT were studied cytogenetically before grafting and serially after transplantation. The 12 European institutions participating in the study, including transplant units and laboratories of cytogenetics, collected a total of 520 studies. The Ph chromosome was observed after BMT in 22 patients who did not enter relapse during the observation time (10-1400 days--median 420 d) following initial detection of the chromosome. This abnormality was observed in 1 to 30% of the cells analyzed. In 10 patients, abnormal cells were detected only within the first 90 d after BMT, in 5 patients both before and after 90 d and in 7 patients only after 90 d. 44% of these 22 patients had a moderate-to-severe cGVHD. Future studies are needed in order to better evaluate the real incidence of persistent disease and the correlations with the GVHD.

Adolescent↗

PubMed2002

BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study.

BACKGROUND: BCR-ABL, a constitutively activated tyrosine kinase, is the oncogene that causes Philadelphia-chromosome-positive (Ph+) leukaemia. STI571, a competitive inhibitor at the ATP-binding site of BCR-ABL, has been shown to have high activity in this type of leukaemia. However, most patients with advanced disease relapse despite continued treatment with STI571. We aimed to find out whether point mutations in BCR-ABL cause resistance to STI571. METHODS: We analysed clinical samples from eight patients resistant to STI571-who had advanced-stage Ph+ leukaemia-for mutations within the ATP-binding site and activation loop of BCR-ABL. Analysis was done before treatment with STI571 and at time of relapse. FINDINGS: We identified five distinct point mutations in the BCR-ABL kinase domain in seven patients. All point mutations arose at positions that have proved to be important for drug binding and have conferred resistance to STI571 in vitro. All patients with mutations had lymphoid leukaemia. INTERPRETATION: Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease.

Benzamides↗

PubMed2003

Perspectives on the treatment of chronic phase and advanced phase CML and Philadelphia chromosome positive ALL(1).

Chronic myeloid leukaemia (CML) is a malignant disease of the bone marrow characterised by the presence of the Philadelphia (Ph) chromosome. About 20% of acute lymphoblastic leukaemia (ALL) patients also show this genetic abnormality. A new drug, imatinib (Glivec, Novartis Pharma AG, Basel, Switzerland, and formerly STI571) is having a profound effect on the treatment and management of all stages of CML and Philadelphia chromosome positive (Ph+) ALL. New treatment algorithms are being developed. Should imatinib replace or be combined with existing therapies? To address this question, we review the pros and cons of therapy with interferon-alpha (IFN-alpha), allogeneic transplantation, autologous transplantation, imatinib, and in the case of Ph+ ALL, chemotherapy and experimental approaches. Conservative and aggressive treatments will be discussed and new molecular methods of monitoring cytogenetic response and their significance will also be reviewed.

Antineoplastic Agents↗

PubMed1986

Hypertriglyceridemia and lipid inclusions in a case of Philadelphia chromosome-positive, acute nonlymphocytic leukemia.

We report a case of a 71-year-old female patient with an unusual morphological variant of Philadelphia chromosome-positive, acute nonlymphocytic leukemia. The myeloblasts exhibited an extreme degree of lipid vacuolization and the serum exhibited hyperlipidemia. The initial serum triglyceride level was 756 mg/dL. There were 26,000 white blood cells per cubic millimeter with 19% myeloblasts. The bone marrow contained greater than 80% myeloblasts that were myeloperoxidase- and chloracetate esterase-positive and typed positive for OKM1 and Leu 1 myeloid cellular markers. At remission, the lipid inclusions disappeared and the serum triglyceride levels returned to normal. Both abnormalities recurred at relapse. The cause of the hyperlipidemia and lipid inclusions was most likely an acquired hyperlipoproteinemia and secondary absorption of lipids into the malignant cells.

Acute Disease↗

PubMed2004

Prognostic significance of additional cytogenetic abnormalities in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia treated with interferon-alpha: a Cancer and Leukemia Group B study.

Secondary cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) have been associated with an inferior outcome in reported series of largely chemotherapy-treated patients. To date, no study has specifically focused on the prognostic significance of secondary karyotypic abnormalities, detected at the time of diagnosis, in interferon (IFN)-alpha treated patients. We compared the outcome of 29 newly diagnosed Ph+ CML patients with additional abnormalities to that of 234 sole Ph+ patients, treated on CALGB protocols with IFN-alpha alone or together with IFN-gamma or low-dose cytarabine. Complete and partial cytogenetic responses were achieved in 20 and 19% of sole Ph+ patients, compared to 23 and 18%, respectively, of patients with additional abnormalities (P=1.00). None of 4 patients with 'high-risk' secondary abnormalities [+8, +Ph and i(17)(q10)], for whom follow-up cytogenetic samples were available, achieved a cytogenetic response. With a median follow-up of 11.3 years, the median overall survival (OS) was 6.0 years for sole Ph+ patients compared to 7.5 years for patients with additional abnormalities (P=0.70), with corresponding 8-year OS of 36 and 38%, respectively. On multivariable analysis, only age (P<0.001) and white blood cell count (P=0.02) were associated with outcome. We conclude that, with the possible exception of +8, +Ph and i(17)(q10), additional chromosomal abnormalities at diagnosis are not associated with inferior outcome in Ph+ CML patients treated with IFN-alpha-based therapy.

Adolescent↗

PubMed1995

Mutations causing high basal level transcription that is independent of transcriptional activators but dependent on chromosomal position in Saccharomyces cerevisiae.

Two single (bel2 and bel4) and two double (bel3 bel7 and bel5 be16) mutations causing enhanced transcription of a gene fusion, consisting of the open reading frame of PHO5 connected to the HIS5 promoter (HIS5p) integrated at the ura3 or leu2 locus, were isolated from a gcn4-disrupted mutant of Saccharomyces cerevisiae. The PHO5 gene, encoding repressible acid phosphatase, in the HIS5p-PHO5 construct was derepressed under amino acid starved conditions by the action of the transcriptional activator Gcn4p. The bel mutants showed temperature-sensitive cell growth and/or cell aggregation. All the mutants except bel4 also showed high levels of transcription of an intact PHO5 DNA integrated at the URA3 locus in the absence of the cognate transcriptional activator, Pho4p, and in the absence of upstream activating sequences of PHO5. The HIS5 and PHO5 genes at their original chromosomal positions were, however, not affected by the bel2 mutation. The BEL2 gene was found to be identical with SIN4/TSF3, mutations in which cause high levels of transcription of the HO and GAL genes in the absence of their respective transcriptional activators, Swi5p and Gal4p. The effect of the bel2/sin4/tsf3 mutation on PHO5 transcription was additive with the Pho4p function. Thus the effect of the bel2/sin4/tsf3 mutation is dependent on the position of PHO5 in the chromosome and independent of Pho4p and Gen4p activation.

Alleles↗

PubMed1999

Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission.

Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections.

Adult↗

PubMed2005

Establishment and characterization of A novel Philadelphia-chromosome positive chronic myeloid leukemia cell line, TCC-S, expressing P210 and P190 BCR/ABL transcripts but missing normal ABL gene.

A novel Philadelphia-chromosome positive (Ph+) cell line, TCC-S, has been established from a patient with Ph+ chronic myeloid leukemia (CML) in the blastic crisis. TCC-S cells were shown to express both P210 and P190 BCR/ABL transcripts by reverse transcriptase-polymerase chain reaction (PCR), although quantitative-PCR revealed that TCC-S cells mainly expressed P210 BCR/ABL transcript. Karyotype analysis revealed several triploid clones which constantly harbored two der(9)del(9) (p12)t(9;22) (q34;qll)s and two del(9) (q21)s. The der(9)del(9) (p12)t(9;22) (q34;q11) is rarely found in other CML cell lines. Moreover, to the best of our knowledge, del(9) (q21) resulting in missing of a restrict region including normal ABL gene has not been found among CML cell lines previously described. Thus, TCC-S cells with only BCR/ABL gene and no normal ABL gene may be a useful tool for functional study of ABL in Ph+ CML.

Blast Crisis↗

PubMed1993

Therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia: possible use of interferon on the basis of some novel concepts.

Current understanding of molecular genetics enables the establishment of new categories based on pathogenesis. Philadelphia (Ph) chromosome-positive leukemia has been reclassified into two molecularly distinct subsets, and the leukemogenesis at the cell level might be linked to the molecular changes. Therefore, treatment for leukemia patients with Ph chromosome could be based on the molecular characteristics. In this review, we discuss the strategy of treating patients with Ph-positive acute lymphoblastic leukemia and the benefit of the combined modality of interferon and chemotherapy.

Adult↗