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PubMed2005

Overproduction of BCR-ABL induces apoptosis in imatinib mesylate-resistant cell lines.

BACKGROUND: Imatinib mesylate, a BCR-ABL tyrosine kinase inhibitor, induces apoptosis in chronic myeloid leukemia cells. Resistance to imatinib is currently the most important concern of this treatment. One of the main mechanisms of this resistance is overexpression of BCR-ABL. METHODS: In the current study, the authors investigated the correlation between BCR-ABL overexpression and apoptosis in BaF/BCR-ABL and LAMA84 cell lines resistant to imatinib suddenly deprived of the inhibitor, and compared with their sensitive counterpart. RESULTS: Removal of imatinib from culture medium led to a decrease in Bcr-Abl protein expression by Day 5, which was sustained for > or = 3 weeks of imatinib deprivation. Apoptosis was observed after 3 days of imatinib deprivation in resistant lines accompanied by caspase activation, loss of membrane asymmetry (annexin V staining), and alteration of mitochondrial potential (dihexyloxacarbocyanine iodide [DiOC6]). Transient activation of the STAT5/Bcl-xL pathway and Akt kinase activity preceded these responses. CONCLUSIONS: Thus, imatinib removal led to apoptosis of BCR-ABL-overexpressing leukemic cells, a phenomenon that could be exploited to sensitize imatinib-resistant cells to the cytotoxic effect of other drugs.

Antineoplastic Agents↗
PubMed1992

Ph-positive chronic myeloid leukemia with loss of the segment distal to M-bcr.

We describe a patient with chronic myeloid leukemia (CML) and a 22q- but no 9q+ chromosome. Southern blot analysis showed a BCR rearrangement. The patient soon developed profound and superficial thrombophlebitis in arms and legs and died from pulmonary embolisation 15 days after diagnosis. Five CML cases with a deletion of 22q but no known translocation of 22q11----qter have been described earlier. The present patient is the first such case, however, in whom a BCR rearrangement has been demonstrated.

Blast Crisis↗
PubMedDate not supplied

Transfection of the bcr/abl oncogene into factor-dependent cells by electroporation: acquisition of autonomous proliferation.

In order to clarify the function of P210 bcr/abl oncogene in leukemogenesis, IL-3 dependent murine hematopietic cell line, FDC-P2, was transfected with the plasmid containing cDNA of P210 bcr/abl oncogene (pGD'210) or murine IL-3 (pcDmIL3) by electroporation. Four out of five pGDH210 transfected clones as well as FDC-P2 transfected with pcDmIL3, acquired autonomous proliferation (i.e. lost the requirement for IL-3 supplementation). The expression of bcr/abl oncogene was weak in one clone, which remained dependent on IL-3. Unlike pcDmIL3 transfectants, which secrete IL-3 into the supernatant, IL-3 was not demonstrated in the culture supernatant of pGD'210 transfected FDC-P2. These finding suggest that P210 bcr/abl oncogene is directly associated with autonomous proliferation, which is the first process of leukemogenesis.

Animals↗
PubMed1989

The accelerating role of Abelson murine leukemia virus in murine plasmacytoma development: in vitro infection of spleen cells generates donor-type tumors after transfer to pristane-treated BALB/c mice.

The role of Abelson murine leukemia virus (A-MuLV) in the accelerated development of murine plasmacytomas (PCs) (Potter et al., 1973: Science, 132, 592-594) was studied in a new experimental system. Spleen cells from pristane-treated or untreated BALB/c mice carrying Robertsonian 6;15 fusion chromosomes were infected in vitro with helper-free A-MuLV overnight and subsequently transplanted into the peritoneal cavity of pristane-treated or untreated BALB/c mice. Donor-derived PCs developed in 4 out of 76 pristane-treated recipients [latent periods: 38-82 (mean 51) days] that had received spleen cells from pristane-treated donors, and also in 2 out of 41 pristane-treated recipients that had received untreated donor-derived spleen cells (latent periods: 65 and 120 days). Three of the PCs in the former and both PCs in the latter group were tested for integration and expression of the v-abl gene, with positive results. This indicates that the spleen contains PC-precursor cells that can be activated by A-MuLV even before the impact of pristane. All 6 donor-origin PCs carried a translocation involving chromosome 15, band D2/3. Four of these corresponded to a typical 12;15 translocation, one was a variant 6;15 translocation and the 6th may represent a previously unidentified translocation between chromosome 15 and the lambda gene-carrying chromosome 16. No PCs developed among 29 pristane-untreated recipients that had received pristane-treated donor-derived spleen cells. In addition to PCs, monocytic tumors developed in 37 (26%) of all recipients. Their development was independent of pristane treatment of recipients but was particularly frequent in those who had received spleen cells from pristane-treated donors.

Abelson murine leukemia virus↗
PubMed2004

New basic discoveries and frontiers in diagnosis, prognosis and prediction of response to therapy in human thyroid, urinary bladder, and prostate tumors.

The fourth edition of this workshop mainly focused on three different human oncotypes, which included thyroid, urinary bladder, and prostate tumors as clinical models to gain new basic knowledge on tumor diagnosis, prognosis, and treatment. At the previous editions (Giordano et al., 2000, J Cell Physiol 183:284-287; Giordano et al., 2001, J Cell Physiol 188:274-280; Giordano et al., 2002, J Cell Physiol 191:362-365), leaders in the fields of pathology, clinical oncology, and basic research presented and discussed the most recent and prevalent findings in such neoplasms from a basic and clinical perspective. A concept that has been widely proposed is that the analysis of intrinsic biological factors displayed by primary tumors may be a valid method for diagnosing different neoplasias and for measuring both their aggressiveness and response to therapy. To date, however, no single prognostic factor, such as oncogenes, suppressor genes, or genes involved in the control of the cell cycle and/or apoptosis has yet proven to be potent enough to be used in clinical practice as a prognostic and predictive factor. The new possibility to simultaneously analyze the expression of the complete repertoire of human genes and a large number of proteins could offer a new scenario in tumor classification, allowing for the formulation of a list of genes able to define a "signature" of tumor outcome. Moreover, starting from data obtained from biomolecular tumor analyses, it has been demonstrated that with this approach, it is also possible to design future therapeutic strategies.

Animals↗
PubMed2001

Theoretical versus experimental resolution in optical microscopy.

The aim of this article is to compare experimental resolution under different conditions with theoretical resolution predicted using electromagnetic diffraction theory. Imaging properties of fluorescent beads of three different diameters (0.1 microm, 0.2 microm, and 0.5 microm) as well as imaging properties of four different fluorescence-stained DNA targets (ABL gene, BCR gene, centromere 6, and centromere 17) are studied. It is shown how the dependence of the resolution on object size varies with wavelength (520 nm versus 580 nm), type of microscopy (wide-field, confocal using Nipkow disk, confocal laser scanning) and basic image processing steps (median and gaussian filters). Furthermore, specimen influence on the resolution was studied (the influence of embedding medium, coverglass thickness, and depth below the coverglass). Both lateral and axial resolutions are presented. The results clearly show that real objects are far from being points and that experimental resolution is often much worse than the theoretical one. Although the article concentrates on fluorescence imaging using high NA objectives, similar dependence can also be expected for other optical arrangements.

DNA↗
PubMed2002

In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups.

BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases. RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients. CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Does the bcr/abl-mediated increase in the efficacy of DNA repair play a role in the drug resistance of cancer cells?

BCR/ABL oncogenic tyrosine kinase is responsible for the pathogenesis of Philadelphia chromosome-positive human leukemia and is generated by a specific reciprocal chromosome translocation, t(9;22)(q34-;q11+). We examined the role of DNA repair in therapeutic drug resistance to idarubicin in the murine pro-B lymphoid cell line BaF3 and its BCR/ABL -transformed clone. These cells can be used as models of human leukemias. The MTT assay revealed that BCR/ABL -transformed cells displayed resistance to idarubicin in the range 0.3-0.5 microm, compared with the control BaF3 cells. Idarubicin at 0.3 and 1 microm induced DNA damage in the form of strand-breaks and/or alkali labile sites in both transformed and control cells in comet assays. The BCR/ABL -transformed cells needed only 60 min to remove damage to their DNA, whereas controls took 120 min. We hypothesize that this observed increase in the efficacy of repair in BCR/ABL- positive cells is involved in their resistance to idarubicin.

Animals↗
PubMed1988

Expression of the protooncogenes in psoriatic lesions.

The expression of cellular protooncogenes in psoriatic lesions was studied. RNA isolated from involved skin of psoriatic patients was subjected to dot-blot hybridization with cloned viral Ki-ras, myc, abl, fos, src, erbB, mos, sis, fes, and yes oncogenes. RNA isolated from the aortal epithelium, peripheral blood lymphocytes, and skin of the nonpsoriatic patients was used as control. The results indicate that the expression of Ki-ras, myc, fos, and abl genes is elevated in psoriatic lesions. The data of this work suggest that the activity of cellular oncogenes may play an important role in the development of psoriasis.

Gene Expression Regulation↗
PubMed2001

Molecular biology of chronic myeloid leukemia.

Multistep carcinogenesis is exemplified by chronic myeloid leukemia with clinical manifestation consisting of a chronic phase and blast crisis. Pathological generation of BCR-ABL (breakpoint cluster region-Abelson) results in growth promotion, differentiation, resistance to apoptosis, and defect in DNA repair in targeted blood cells. Domains in BCR and ABL sequences work in concert to elicit a variety of leukemogenic signals including Ras, STAT5 (signal transducer and activator of transcription-5), Myc, cyclin D1, P13 (phosphatidylinositol 3-kinase), RIN1 (Ras interaction/interference), and activation of actin cytoskeleton. However, the mechanism of differentiation of transformed cells is poorly understood. A mutator phenotype of BCR-ABL could explain the transformation to blast crisis. The aim of this review is to integrate molecular and biological information on BCR, ABL, and BCR-ABL and to focus on how signaling from those molecules mirrors the biological phenotypes of chronic myeloid leukemia.

Animals↗
PubMed2003

Correlation between BCR-ABL expression and tumor burden is restricted to the transition from minor to major cytogenetic response in interferon treated CML patients.

The interferon treatment of chronic myeloid leukaemia has been monitored by investigating the tumour burden as revealed by fluorescence in situ hybridization and the expression of BCR-ABL chimera determined by quantitative reverse transcription polymerase chain reaction. These parameters were obtained from the peripheral blood of 51 untreated and 104 follow-up patient samples. Poor correlation (r=0.31) was found between BCR-ABL expression and tumor load in all samples as well as in untreated patients, and this correlation was even less in all follow-up cases (r=0.28). Regarding chimera expression five order of magnitude difference existed in the untreated patients and this value dropped to two in those with complete cytogenetic response. Only the major and the complete cytogenetic response groups differed significantly (p<0.001) in the BCR-ABL expression from that of patients at diagnosis. Among the different cytogenetic response groups the only significant difference (p<0.01) in the BCRABL expression was obtained between the major and the minor responders. In the individual patients not only correlated changes of residual tumour mass and chimera expression, but mainly independent changes of these two parameters were observed. This indicates that the BCR-ABL expression and the tumor burden are largely independent variables.

Antineoplastic Agents↗
PubMed2002

A case of biphenotypic blast crisis of unclassified myeloproliferative disorder.

We report a first case of biphenotypic blast crisis of unclassified myeloproliferative disorder (MPD). A 20-year-old patient presented with fever, splenomegaly, marked leukocytosis (603 x 10(3)/ micro l), and blasts in the peripheral blood. Since Ph chromosome and bcr-abl gene rearrangement were absent, the diagnosis of an unclassified MPD in the blast crisis phase was established. Immunophenotyping confirmed a biphenotypic crisis of myeloid and T-lymphoid antigens. The patient went into a complete remission after chemotherapy, but marked granulocytic hyperplasia (M:E ratio of 5.7) and 90% cellularity remained. Blast crisis recurred during subsequent intensification chemotherapy and the patient did not go into a complete remission regardless of the intense chemotherapy. The blast crisis transformed from unclassified MPD had a grave prognosis as it responded poorly to chemotherapy. This unique blast crisis is distinguishable from the blast crisis of chronic myelogenous leukemia.

Adult↗
PubMed1999

Molecular pathogenesis of chronic myeloid leukemia: implications for new therapeutic strategies.

With an annual incidence of about ten in 1,000,000 people, chronic myeloid leukemia (CML) accounts for most cases of myeloproliferative disease and for 20% of all leukemias. While novel therapies such as treatment with interferon-alpha or bone marrow transplantation have successively improved the outcome of CML treatment, hope for future progress in the therapy of CML lies in an almost unique feature of this hematological malignancy. In contrast to many other forms or subforms of leukemias which display a great diversity in chromosomal alterations, most cases (>95%) of CML seem to be caused by an almost invariably found cytogenetic aberration, the so-called Philadelphia chromosome (Ph), resulting in the bcr-abl fusion gene. Its gene product, p210bcr-abl (Bcr-Abl), is believed to be essential for hematopoietic cell transformation and seems to exert its effects by interfering with cellular signal transduction pathways, normally involved in the control of cell death and proliferation. Several partially interacting pathways have been shown to be induced by Bcr-Abl. The role of most of them is still unclear and, as understanding their biological functions should lead to novel therapeutic strategies on a molecular basis, much effort is spent on identifying their precise roles in CML. This review focuses on our current understanding of Bcr-Abl-induced signal transduction and outlines its importance for the biological effects of Bcr-Abl.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Biologically-based risk estimation for radiation-induced chronic myeloid leukemia.

Radiation cancer risks are typically determined by the use of simple statistical descriptions of epidemiological data. It is important in risk assessment in general, however, to attempt to incorporate as much biological information into the risk models as possible. We illustrate this by presenting a biologically-based linear-quadratic-exponential (LQE) incidence rate model for radiation-induced chronic myeloid leukemia (CML). The model consists of a linear-quadratic dose-response for the induction of BCR-ABL, a waiting time distribution between BCR-ABL formation and detection of CML, and an exponential cell-killing term that multiplies both the background and induced incidence rates. Using data exclusive of the A-bomb survivor cohort, Bayesian priors are defined for each of the nine parameters in this LQE model. The priors are based on chromosomal translocations in lymphocytes, hematopoietic stem cell survival experiments, CML waiting times in women irradiated for benign disease, the background CML incidence rate in the U.S. population, and genomic DNA target sizes of BCR and ABL. Fixing three of the LQE model parameters to the means of their priors, maximum likelihood estimates of the remaining six parameters were obtained using A-bomb survivor incidence data for Hiroshima males. The likelihood estimates and the corresponding six prior distributions, both approximated as multivariate normal, were then used to form Bayesian posteriors for the six parameters not fixed. With these posteriors the LQE model yields Qgamma*=0.0042 Gy(-1) where Qgamma* is the upper 95% confidence bound of the lifetime CML risk per person-gray in the limit of low doses of gamma-rays. This value is slightly less than Qgamma*=0.0049 Gy(-1) obtained from likelihood estimates of the LQE parameters, and substantially less than Qgamma*=0.0158 Gy(-1) obtained for a simple statistical model linear in dose for kermas less than 4 Gy.

Algorithms↗