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PubMed2003

Acute Philadelphia chromosome-positive leukemia in an adolescent boy after liver transplantation.

Acute leukemia is an untoward event following immunosuppression for solid organ transplantation and is related to the oncogenic effects of Epstein-Barr viral infections. The authors report a case of acute, Philadelphia chromosome-positive, T-cell lymphoblastic leukemia following liver transplantation. Molecular typing demonstrated a minor bcr-abl rearrangement (190 kD), which persisted in remission in 71% of peripheral neutrophils as determined by fluorescence in situ hybridization. The authors conclude that this patient may have presented in a lymphoid blast crisis of chronic myelogenous leukemia with an acute T-cell leukemia/lymphoma syndrome.

Adolescent↗
PubMed2004

[Prognostic efficacy for measurement of real-time quantitative PCR-based major bcr/abl mRNA in patients with Philadelphia chromosome-positive leukemia].

Evaluation of minimal residual disease (MRD) provides prognostic information on various hematological malignancies. We describe here the prognostic efficacy of real-time quantitative polymerase chain reaction (RQ-PCR)-based analysis of major bcr/abl mRNA in cases of Philadelphia chromosome-positive leukemia (Ph-leukemia). Twenty-one patients with Ph-leukemia were enrolled as subjects to determine the usefulness of RQ-PCR-based measurement of bcr-abl/abl ratios. Imatinib mesylate (imatinib) was administered to seven of the 21 patients before allogeneic stem cell transplantation (SCT). Hematological relapse or failure of treatment with SCT was observed in 2 of those patients who showed bcr-abl/abl ratios of more than 0.002%, and 5 of the 7 patients showed both RQ-PCR and RT-PCR negativity immediately after SCT. All of the 5 patients who did not receive imatinib before allogeneic SCT showed RQ-PCR negativity immediately after SCT, but the results of RT-PCR were positive in 3 patients at the same time points, and those became negative after donor lymphocyte infusion or the appearance of graft-versus-host disease. Administration of imatinib before SCT was thought to induce an early remission. On the other hand, 8 patients who received imatinib without SCT showed a remarkable decrease in bcr-abl/abl ratios. The ratio gradually rose in one patient with Ph+ALL, enabling prediction of the hematological relapse preceding detection by fluorescence in situ hybridization (FISH) analysis. Standardization of RQ-PCR analysis of bcr-abl mRNA will help to predict early hematological relapse in patients with MRD. In conclusion, it is thought that measurement of RQ-PCR-based major bcr/abl mRNA in patients who were given imatinib and were treated with SCT is useful for the evaluation of MRD and in deciding additional treatment.

Adult↗
PubMed2002

Increased circulating normal and BCR-ABL+Ve progenitor numbers in Philadelphia chromosome-positive acute myeloid leukaemia.

We recorded elevated numbers of circulating myeloid and erythroid colony-forming cells in 15 adult patients with acute myeloid leukaemia (AML) who presented with high blood white cell counts. Since leukaemic blasts from three of these patients were Philadelphia chromosome-positive (Ph+), we were able to determine if blood progenitors from these particular patients arose from the leukaemic clone or from residual normal progenitors. Blasts and colonies were intensively investigated using a combination of cell surface marker analysis by flow cytometry, RT-PCR and interphase fluorescence in situ hybridization (FISH). FISH detected rearrangements within the major breakpoint BCR (M-BCR) region in blasts and in some myeloid and erythroid colonies from patients 1 and 2. The minor breakpoint (m-BCR) region was detected in blasts and in some myeloid and erythroid colonies from patient 3. RT-PCR detected long b2a2 BCR-ABL transcripts in blasts from patients 1 and 2, although misspliced short e1a2 transcripts were also seen in patient 1. Only e1a2 transcripts were found in blasts from patient 3. Flow sorting demonstrated the B-cell marker CD19 on blasts and on a proportion of myeloid and erythroid progenitors from patients 1 and 3. RT-PCR also detected IgH rearrangements, further evidence of B-cell differentiation, in blasts from these two patients. We conclude that both normal and clonal circulating progenitor numbers can be raised in both M-BCR and m-BCR Ph+ AML. The underlying cause, perhaps efflux from a congested marrow, may be common to AML patients with a high blood white cell count.

Acute Disease↗
PubMed2004

Existence of leukemic clones resistant to both imatinib mesylate and rituximab before drug therapies in a patient with Philadelphia chromosome-positive acute lymphocytic leukemia.

Imatinib mesylate and rituximab are molecularly targeted drugs against the BCR-ABL fusion protein and the CD20 antigen, respectively. Although these drugs have excellent anticancer effects, a major concern is drug resistance. We have investigated the case of a patient with Philadelphia chromosome-positive and CD20+ acute lymphocytic leukemia who acquired resistance to imatinib and rituximab. Imatinib therapy resulted in prompt cytogenetic remission, but resistance developed shortly thereafter. Sequencing of the kinase domain of the ABL gene and allele-specific polymerase chain reaction analysis revealed a point mutation resulting in an E255V substitution that was present before the therapy. After the patient received mild chemotherapy followed by rituximab administration, hematologic and cytogenetic remission was sustained for 5.5 months. The recurrent leukemic cells after the rituximab therapy showed not only the E255V mutation in the ABL gene but also loss of the CD20 antigen due to impaired transcription of the CD20 gene. The results of 2-color flow cytometry analysis showed that a small population of CD20(-) leukemic cells existed before the imatinib therapy. These results suggest that leukemic subclones carrying a genetic perturbation of the targeted molecules for both imatinib and rituximab were present before the therapies. The preexistence of primary resistant clones suggests the inability of combination therapy with 2 molecularly targeted drugs to overcome drug resistance in leukemia.

Aged↗
PubMed2004

Simultaneous analysis of cytoskeletal patterns and chromosome positioning in human fertilization failures.

OBJECTIVE: To sequentially and reliably apply both tubulin immunocytochemistry (ICC) and fluorescence in situ hybridization (FISH) to human fertilization failures, thus providing a tool for a multiple analysis of arrest. DESIGN: Analysis of human fertilization failures at several stages of arrest. SETTING: Academic and clinical institutions. PATIENT(S): Consenting patients undergoing assisted reproduction technologies. INTERVENTION(S): Failed fertilizations displaying signs of activation without pronuclear development, or with the absence of polar body emission or cleavage 48 hours after insemination or microinjection were analyzed. Fertilization failures were fixed and processed for ICC. After data was collected the same samples were then subjected to FISH analysis using probes for chromosomes X, Y, and 18. MAIN OUTCOME MEASURE(S): Simultaneous ICC and FISH data on the same sample. RESULT(S): Sequential application of straightforward standard ICC and FISH techniques was not possible, as the morphologic features had been altered, microtubular patterns were not preserved, and many samples were rendered opaque. Only chromatin at the cell surface or outside the oocyte/zygote, such as metaphase II spindles or polar body nuclei, could be routinely probed for FISH after ICC. However, an increase in detergent-induced sample permeabilization as well as the removal of several steps usually performed for FISH made it possible to directly compare microtubular patterns and chromosome position, regardless of chromatin status. CONCLUSION(S): Analysis of specific proteins by immunocytochemistry and of chromosome status/positioning by FISH can be carried out sequentially in human fertilization failures, irrespective of the stage of arrest.

Blastocyst↗
PubMed1998

Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome.

Among 4,760 acute lymphoblastic leukemia (ALL) patients enrolled from 1986 to 1995 in two subsequent trials of the BFM and AIEOP study group, 61 patients were found to have Philadelphia chromosome-positive (Ph+) ALL. These patients were analyzed for presenting features and treatment outcome to identify specific prognostic factors. Treatment stratification was based on initial cell mass and early response as determined by blast count in peripheral blood after a 7-day induction prephase with prednisone and one dose of intrathecal methotrexate on day 1. All patients were treated by similar intensive Berlin-Frankfurt-Münster (BFM) protocols. The median age of Ph+ patients was 7.5 years, the median white blood cell count (WBC) was 75 x 10(9)/L, 77% of patients had common ALL, and 29% coexpressed myeloid markers. After a median observation time of 4.2 years, 29 of 61 patients are alive (survival probability [pSUR] at 4 years, 0.49; standard error [SE], 0.06), and 24 of 61 are in first complete remission (CR1; probability of event-free survival [pEFS] at 4 years, 0.38; SE, 0.06). Twenty (35%) of 57 evaluable patients had >/=1,000 leukemic blasts per microliter of blood on day 8 of induction (defined as prednisone-poor-response [PPR]). These patients were older (10.0 v 6.88 years; P = .02) and had a higher WBC (144 v 29 x 10(9)/L; P = .0016) as compared with patients with prednisone good response (PGR; <1,000 blasts/microL at day 8). Only 2 of 20 patients (10%) with PPR remained in CR1 and alive: 6 patients with PPR did not survive after allogeneic bone marrow transplantation (BMT) due to recurring disease (n = 3) and toxicity (n = 3), and 12 nontransplanted patients died due to progression (n = 5) or relapse (n = 7). In contrast, 26 (70%) of the 37 patients with PGR are alive. Of 18 patients transplanted by allo-BMT, 1 relapsed (now in CR2) and 4 died after BMT. Among the 19 patients with PGR treated by chemotherapy alone, 8 remained in CR1 and 11 relapsed, of which 4 are in CR2 or CR3. The prednisone response emerged as the only independent prognostic factor for survival in Cox regression analysis. Thus, two thirds of Ph+ childhood ALL cases can be identified early by PGR, which, when treated with intensive BFM chemotherapy, with or without BMT, have a significantly lower risk of treatment failure. With a median continuous complete remission (CCR) time of 4.1 years, pEFS for PGR is 0.55 (SE, 0.08) compared with 0.10 (SE, 0.07) in patients with PPR (P = .0001). PGR is also an indicator for treatment responsiveness and durable second remission after relapse, which in turn may provide a second chance for BMT.

Adolescent↗
PubMed1979

Philadelphia-chromosome-positive pre-B-cell leukemia presenting as blast crisis of chronic myelogenous leukemia.

Cytogenetic studies of chronic myelogenous leukemia (CML) have shown that the majority of hemopoietic cells originate from pluripotential stem cells affected in this disease. Evidence that lymphocytes are also progeny of these stem cells, however, has been indirect. Philadelphia-chromosome-positive leukemic blasts from a 4 10/12-yr-old boy with CML in blast crisis had features characteristic of pre-B leukemic cells, including expression of cytoplasmic IgM and absence of surface immunoglobulin. Additional immunologic, enzymatic, and pharmacologic characterization of these cells supported their pre-B-cell phenotype. Together, these features provide direct evidence for CML stem cell ancestry to lymphocytes of the B-cell lineage.

B-Lymphocytes↗
PubMed1994

The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.

In Drosophila the Notch gene controls differentiation to various cell fates in many tissues. Three mammalian Notch homologs have recently been identified: Notch 1, 2, and 3. All three homologs are very highly conserved relative to the Drosophila Notch gene, which suggests that they are important for cell differentiation in mammals. This notion is supported by the previous finding of a truncated, translocated form of the human NOTCH1 gene (formerly TAN1) in three cases of leukemia. Given this genetic link between NOTCH1 and tumor formation, it is of interest to establish the chromosomal positions of the other two homologs. We report the identification of cosmid clones for the human NOTCH1, 2, and 3 genes. These clones were used as probes in fluorescence in situ hybridization to human metaphase chromosomes, and the results, combined with data from somatic cell hybrid panels, show that the NOTCH2 and 3 genes are located at positions 1p13-p11 and 19p13.2-p13.1, respectively, which are regions of neoplasia-associated translocation.

Amino Acid Sequence↗
PubMed2005

Variant translocation with a deletion of derivative (9q) in a case of Philadelphia chromosome positive (Ph +) essential thrombocythemia (ET), a variant of chronic myelogenous leukemia (CML) with a poor prognosis.

Patients presenting with thrombocytosis require thorough clinical and laboratory evaluation to determine whether they suffer from essential thrombocythemia or another myeloproliferative disorder. This distinction becomes increasingly relevant as targeted agents become available to treat specific myeloproliferative diseases. Cytogenetic testing plays a major role in this analysis. This study presents a patient with Philadelphia chromosome positive (Ph + ) thrombocytosis and a cryptic der(9q)t(5;9)t(9;22) not found by conventional cytogenetics, whose disease progressed within 2 years to typical myeloblastic crisis of CML. It discusses the entity of Ph + ET, the utility of molecular cytogenetic testing in the diagnosis of this unusual disease entity and the importance of cytogenetic testing in the prognosis of ET.

Aged↗
PubMed1996

Human thioredoxin reductase gene localization to chromosomal position 12q23-q24.1 and mRNA distribution in human tissue.

Thioredoxin reductase is a member of the pyridine nucleotide-disulfide oxidoreductase family of enzymes. By delivering reducing equivalents to thioredoxin, thioredoxin reductase exerts control over a number of redox-sensitive factors in the cell, including ribonucleotide reductase and several transcription factors. We have localized the human thioredoxin gene to chromosomal position 12q23-q24.1 by in situ hybridization. We have also determined the relative tissue distribution of thioredoxin reductase mRNA as well as thioredoxin mRNA by probing a Northern blot of several human normal tissues.

Chromosome Banding↗
PubMed1994

Antisense BCR-ABL oligonucleotides induce apoptosis in the Philadelphia chromosome-positive cell line BV173.

BCR-ABL antisense oligonucleotides can specifically reduce colony formation of early hematopoietic progenitor cells from chronic myeloid leukemia (CML) patients. Little is known about the mechanism of this inhibition. We studied the inhibition of the bcr-abl oncogene using fluorescein-labeled phosphorothioate oligonucleotides in the Philadelphia chromosome-positive cell line BV173. Oligonucleotide stability, uptake, bcr-abl mRNA degradation, inhibition of cell proliferation, and cell death were studied. The oligonucleotide uptake was directly dependent on the extracellular concentration and was constant over the first 18 h of incubation. After that the uptake rate decreased. We detected a decrease in bcr-abl mRNA after 3 days of treatment with antisense oligonucleotides, but much less in controls. The controls used in the experiments were the sense oligonucleotide, equimolar amounts of sense and antisense, and an untreated control. Antisense oligonucleotides completely inhibited cell growth of BV173 cells and did not inhibit growth of HL-60 cells, whereas control oligonucleotides had no such effect on either cell line. An oligonucleotide specific for the other CML breakpoint was also effective in reducing cell growth of BV173. By the use of a DNA double staining technique to discriminate between necrotic and apoptotic cells, we detected a large number of apoptotic cells in antisense treated BV173 cultures after 5 days of treatment as compared to controls. We conclude that antisense BCR-ABL oligonucleotides reduce bcr-abl mRNA expression in BV173 cells mainly in a sequence-specific manner and induce apoptosis.

Apoptosis↗
PubMed1994

Philadelphia chromosome positive acute lymphoblastic leukemia masquerading as persistent asymptomatic bone marrow necrosis.

Bone marrow necrosis is an uncommon histologic finding of malignant diseases at presentation. Clinically it is characterized by pyrexia and severe bone pain, and heralds a poor prognosis if untreated. We report an unusual patient with asymptomatic bone marrow necrosis persisting for 10 mths, a hitherto undescribed length of time for this condition. The diagnosis of Philadelphia chromosome positive acute lymphoblastic leukemia was finally made after multiple bone marrow biopsies.

Aged↗
PubMed2001

Imatinib mesylate: clinical results in Philadelphia chromosome-positive leukemias.

Targeted cancer therapy has long been sought by the oncology community as a potentially better approach than currently available therapies. One targeted therapy that has shown great success is the tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) which was recently approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Basic scientific investigation into the molecular causes and pathogenesis of CML and encouraging preclinical investigations on the mechanism of action of imatinib mesylate led to the initiation of phase I clinical trials. Clinical development of imatinib mesylate continued with three large, multicenter, phase II trials. The majority (88%) of interferon-alpha-resistant or intolerant patients in chronic-phase CML achieved a complete hematologic response to imatinib mesylate. More importantly, approximately half of patients achieved a major cytogenetic response, a result historically associated with improved survival. Furthermore, 21% of patients in accelerated-phase CML and 13.5% of patients in blastic-phase CML (patient populations with typically poor prognosis before the advent of imatinib mesylate) achieved major cytogenetic responses. Results from ongoing studies will determine the durability of these responses and will evaluate ways to optimize treatment in advanced-stage patients using imatinib mesylate in combination with other therapies. Additional trials are planned to investigate the efficacy of imatinib mesylate to treat a variety of solid tumors whose pathogenesis is driven by the other tyrosine kinase targets, c-Kit and platelet-derived growth factor receptor.

Antineoplastic Agents↗
PubMed1998

Intensified conditioning regimen in bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

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.

Adolescent↗
PubMed2000

Evaluation of heterologous insulator function with regard to chromosomal position effect in the mouse blastocyst and fetus.

Insulators are located at the boundaries of differentially regulated genes and delimit their interactions by establishing independent chromatin structures. Recently, an insulator sequence has been found in the 5'-flanking region of arylsulfatase (ARS) gene from sea urchin. To investigate functional conservation of this ARS insulator in mice, we performed blastocyst assays to evaluate the effect of this insulator on the chromosomal position effect, quantitatively. We constructed transgenes that have a luciferase gene under the control of the CMV-IE enhancer and the human elongation factor 1 alpha promoter in the presence or absence of the ARS insulator in both flanking regions. These transgenes were microinjected into 1-cell mouse embryos and luciferase activity was measured at the blastocyst stage. We found that the presence of ARS insulator sequence doubled the number of luciferase-expressing blastocysts, and that the proportion of the blastocysts with high-level expression (> or = 1 x 10(4) relative light units (RLU)) was increased more than tenfold. In the case of transgenic fetuses, however, the presence of ARS insulator did not seem to improve transgene expression. These results suggest that the sea urchin ARS insulator confers position-independent expression driven by the human elongation factor 1 alpha promoter, at least in the blastocyst stage of the mouse.

Animals↗
PubMed2002

Targeted therapies in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ; Glivec, Novartis Pharma AG, Basel, Switzerland), a signal transduction inhibitor with preferential effects against the tyrosine kinase activity of the protein product of the ABL proto-oncogene, induced hematologic responses in >or=90% of patients with chronic-phase chronic myeloid leukemia (CML). In Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event, making it another hematologic malignancy targeted by this ABL-tyrosine kinase inhibitor. In an international multicenter phase II trial, imatinib-induced hematologic responses (typically brief) were achieved in 60% of patients with relapsed or refractory Ph(+) ALL. Subsequently, the German Multicenter Study Group for Adult ALL (GMALL) analyzed 59 patients treated in two successive nonrandomized phase II trials of imatinib in patients with relapsed or refractory Ph(+) ALL. Peripheral blood blasts cell clearance occurred within 8 to 14 days in most patients. However, in a significant proportion, blast counts subsequently increased 16 to 50 days after treatment onset. Imatinib mesylate was particularly effective in patients with relapse after stem cell transplantation (SCT); 75% of patients achieved complete leukemic response. Rapid development of resistance during treatment with imatinib mesylate remains a major problem. Further research efforts should explore the mechanisms of resistance to imatinib mesylate; effectiveness of other targeted therapies (eg, farnesyl transferase inhibitors [FTIs]); combination therapies; and inclusion of strategies for immune response modification (eg, donor lymphocyte infusions, interferon-alpha) for Ph/BCR-ABL-positive leukemias.

Antineoplastic Agents↗
PubMed2003

[Glivec in combination with HA regimen for treatment of 20 patients with Ph chromosome positive acute leukemia].

BACKGROUND & OBJECTIVE: Glivec was approved by Food & Drug Administration (FDA) in May 2001 as a gene target drug for treatment of chronic myeloid leukemia (CML) and showed a good curative effect for patients with chronic myeloid leukemia in chronic phase. But its effectiveness was poor in patients with CML blast phase treated with Glivec alone. Glivec was reported having synergetic effect with other chemical agents in vitro, but there is few report in clinical combined application. In this paper, we analyzed effectiveness of Glivec in combination with homoharringtonine (HHT) and cytarabine (Ara-C) for patients with Ph chromosome positive acute leukemia (Ph(+)-AL), and investigated patients' tolerance to side effects of this trial. METHODS: A total of 20 patients (16 males and 4 females, median age was 43 years) were eligible. Blasts in peripheral blood (PB) or bone marrow (BM) were both more than 30%, bcr/abl fusion genes were detected positive in 90% cells by analysis of karyotype or fluorescence in situ hybridization (FISH). Five patients showed t(9;22) and other 15 patients showed more complicated chromosome abnormality. Of these 20 patients, 17 patients developed Ph(+)-ANLL from CML, 1 case developed Ph(+)-ALL, and other 2 cases were primary Ph(+)-ALL. The median interval from diagnosis to Glivec treatment was 4 months. Eighteen of 20 patients received different chemotherapy regimens for 2-4 treatment cycles, but no one reached hematological complete remission (HCR). All patients were given oral Glivec daily at the doses of 0.3-0.6 g in a median treatment time of 2.5 months (range, 1-6.5 months). Ph(+)-ANLL patients were infused with HHT over 6-24 hours daily at the doses of 1-2 mg intravenously and Ara-C 30-50 mg daily subcutaneously for 10-14 days; 3 patients with Ph(+)-ALL received HOAP or DOP combination treatment regimens (One cycle consists of HA with the same dosage described above for Ph(+)-ANLL patients for 7 days, daunorubicin at the dose of 40 mg/d intravenously for 3 days, vincristine at the dose of 2 mg/wk for two weeks, and prednisone at the doses of 60-80 mg/d for 14 days). Median treatment cycle was 2 (range, 1-3). The dosage of Glivec could be reduced or treatment was suspended when bone marrow inhibition happened. G-CSF was used when necessary. The curative effect was evaluated by international hematology and cytogenetics standards, in which bone marrow was examined every chemotherapy cycle and chromosome was analyzed 3 months later. RESULTS: Among the 20 patients receiving Glivec, 40% achieved HCR, and 25% achieved hematological partial remission (HPR), but only 15% patients approached a partial cytogenetic remission and no cytogenetic responses were found in other 85% patients. White blood cells (WBC) in peripheral blood reduced from 41+/-31 x 10(9)/L to normal level within 1 week. The blasts decreased from (50+/-30)% to(1.9+/-2.9)% (P< 0.001) in median time of 21.0+/-16.8 days. Three patients with high fever recovered normal temperature after 3 days treatment. When follow-up median time at 8 months, the total survival rate reduced to 40%, the rate of death and lost follow-up number of patients added to 60%. CONCLUSION: Regimen of Glivec in combination with HA could increase chemotherapy effect for the patients with Ph(+)-AL, prolong their life time and the side-effects were tolerable.

Acute Disease↗
PubMed1994

Chromosomal position effects in chicken lysozyme gene transgenic mice are correlated with suppression of DNase I hypersensitive site formation.

The complete chicken lysozyme gene locus is expressed copy number dependently and at a high level in macrophages of transgenic mice. Gene expression independent of genomic position can only be achieved by the concerted action of all cis regulatory elements located on the lysozyme gene domain. Position independency of expression is lost if one essential cis regulatory region is deleted. Here we compared the DNase I hypersensitive site (DHS) pattern formed on the chromatin of position independently and position dependently expressed transgenes in order to assess the influence of deletions within the gene domain on active chromatin formation. We demonstrate, that in position independently expressed transgene all DHSs are formed with the authentic relative frequency on all genes. This is not the case for position dependently expressed transgenes. Our results show that the formation of a DHS during cellular differentiation does not occur autonomously. In case essential regulatory elements of the chicken lysozyme gene domain are lacking, the efficiency of DHS formation on remaining cis regulatory elements during myeloid differentiation is reduced and influenced by the chromosomal position. Hence, no individual regulatory element on the lysozyme domain is capable of organizing the chromatin structure of the whole locus in a dominant fashion.

Animals↗