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PubMed1994

The HLA class I-CML association revisited taking into account the two forms of gene fusion in the Philadelphia chromosome. A multicenter study.

CML patients possess either a b3-a2 or a b2-a2 fusion between the BCR and ABL genes. Depending on the type of fusion, two different series of non-self potentially immunogenic peptides may be produced. If they are presented by HLA class I molecules and recognized by cytotoxic CD8 lymphocytes, individuals could be more susceptible or resistant to leukemic cells bearing one or the other form of fusion according to their HLA class I phenotype. To test this point, the frequencies of HLA-A and HLA-B alleles were compared between b3-a2 and the b2-a2 CML patients. In essence, no difference was found whose significance could withstand correction for multiple comparisons.

Base Sequence↗
PubMed1989

9;22 translocation and bcr rearrangements in chronic myelocytic leukemia patients among atomic bomb survivors.

To elucidate the mechanism of leukemia induced by radiation, we studied both chromosome abnormalities and bcr rearrangements of seven CML patients with a history of atomic bomb exposure and 14 CML patients without the exposure. All patients, irrespective of radiation exposure, had 9;22 translocation and rearrangement of the bcr gene in the leukemic cells. Further analysis of breakpoints within the bcr gene demonstrated no distinct difference between the exposed and the non-exposed groups. The present study suggests that formation of the chimeric bcr-abl gene and its genetic products may play an important role in the development of leukemia in either radiation-induced or de novo CML.

Adult↗
PubMed1989

The variable hematologic expression of the BCR-ABL genomic mutation and its possible determinants.

The Philadelphia (Ph) chromosome usually results from the t(9;22), which causes the physical association of the BCR1 and ABL genes and their function as a single new gene. This precise genomic mutation probably has a significant role in the development of leukemia in humans, but that leukemia may take several forms: chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, and essential thrombocythemia; CML also transforms to a lymphoid or myeloid acute phase. Two models are considered with regard to determinants of this variable hematologic expression of BCR-ABL. The first is variation in the breakpoint site of BCR1. Two breakpoint sites, M-BCR and m-BCR, are known, and their occurrence shows a nonrandom association with the different forms of leukemia. The precise position of the breakpoint within M-BCR may also be important. The second model concerns the role of other genes in determining the leukemic form shown by BCR-ABL. Results are reviewed of a patient who entered blast crisis CML and whose leukemic clones involved ten genetic loci with known leukemic associations. Many of these were probably genetic variants that allowed leukemic proliferations following the initiation of blast crisis. The multiplicity of these genes may obscure the prime determinant of blast crisis, which is unknown at the present time.

Gene Expression Regulation, Leukemic↗
PubMed2004

ABL-fusion oncoproteins activate multi-pathway of DNA repair: role in drug resistance?

Chromosomal translocations of tyrosine kinase c-ABL gene from chromosome 9 may generate oncogenic kinases exhibiting constitutive tyrosine kinase activity. Recently, we have shown that ABL-fusion oncogenic tyrosine kinases, BCR/ABL and TEL/ABL, specific to hematopoietic malignances, induced resistance to DNA-damaging agents. To elucidate the role of DNA repair in this phenomenon we examined the capacity of murine BaF3 lymphoid cells and their TEL/ABL-transformed counterparts to repair DNA lesions caused by gamma- and UV-radiations and the anti-cancer drug, idarubicin. TEL/ABL-transformed cells displayed resistance to these DNA damaging agents as evaluated by MTT assay and the survival advantage was associated with an accelerated kinetics of DNA repair as measured by the alkaline comet assay. Deoxyribonucleosides (dNTPs) supplementation of the repair medium further stimulated DNA repair and the effect was specific to the DNA damage agent used in the experiment but only the transformed cells displayed this feature. A variety of damages induced imply the multi-pathway of DNA repair involved. We also examined the capability of BCR/ABL-fusion to modulate the repair of oxidative lesions, considered as a major side effect of various anti-cancer drugs including idarubicin and radiation. Employing the free radical scavenger alpha-phenyl-N-tert-butyl nitrone (PBN, a spin trap) and DNA repair enzymes: endonuclease III (EndoIII) that nicks DNA at sites of oxidized bases, we found that BCR/ABL-transformed cells repaired oxidative DNA lesions more effectively than control cells. Our results suggest, that oncogenic ABL-dependent stimulation of DNA repair may contribute to the cell resistance to genotoxic treatment.

Animals↗
PubMed1990

An E. coli expression system for the rapid purification and characterization of a v-abl tyrosine protein kinase.

A bacterial expression vector containing a segment of the v-abl gene from Abelson murine leukemia virus (A-MuLV) was constructed such that the gag region of v-abl was replaced by a sequence encoding the IgG-binding domain of the S. aureus protein A. pabl HP, a fusion protein encoded by this vector was rapidly purified to near homogeneity by affinity chromatography on IgG-Affigel and Mono Q FPLC. The Km of the pabl HP kinase for ATP varied with [Val5]-angiotensin II concentration and was 21.2 microM at saturating concentrations of [Val5]-angiotensin II. The Km for [Val5]-angiotensin II at saturating concentrations of ATP was 3.8 mM. The turnover number, at 20 degrees C, was 62 mumol min-1 mumol-1. Initial rate studies support a ternary complex kinetic mechanism for phosphoryl transferase. The substrate specificity of the pabl HP kinase was further characterized using synthetic peptides. This expression system, which enables the rapid purification of recombinant v-abl kinase is suitable for the comparative enzymological study of mutant v-abl enzymes generated by site-directed mutagenesis.

Abelson murine leukemia virus↗
PubMedDate not supplied

Rearrangements of immunoglobulin- and BCR-genes in chronic myeloid leukemia.

Clonal rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes have been demonstrated in malignant lymphoid tumors of B and T cell origin. In Philadelphia chromosome (Ph1) positive chronic myeloid leukemia (CML) the bcr and c-abl genes are reorganized and a new transcript, composed of both genes is expressed. Immunoglobulin gene rearrangements were also detected in lymphoid blast crisis but not in myeloid blast crisis of CML. We analyzed in Southern blot experiments whether Ig and TCR rearrangements could also occur in the chronic or accelerated phase of the disease. Our results indicate that immunoglobulin but not TCR delta or TCR gamma gene rearrangements also occurred in some patients with CML in chronic and accelerated phase but not in myeloid blast crisis, together with rearrangements of the bcr gene.

Adult↗
PubMed2005

Cytogenetic characterization of a BCR-ABL transduced mouse cell line.

Most patients with Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) show evidence of secondary chromosome aberrations that may influence the course of disease and response to treatment. To better understand how these secondary chromosomal aberrations occur and to investigate whether the p185/p190 BCR-ABL fusion protein may directly induce an increased chromosomal instability and subsequently the appearance of clonal chromosome aberrations, three BRC-ABL (p185/ p190)-transduced mouse pre-B cell lines were analyzed by spectral karyotyping and fluorescence in situ hybridization. The human wild-type BCR-ABL gene was expressed at a level comparable with that in human Ph-positive leukemias at diagnosis. All BCR-ABL-transduced cell lines acquired similar clonal chromosomal aberrations. Trisomy 5 was always present, followed by loss of the Y chromosome, trisomy of chromosomes 12 and 18, and an unbalanced translocation between chromosomes X and 12. Thus, ectopic p185/p190 BCR-ABL expression, such as p210 BCR-ABL, PML-RARA, or C-MYC transduction, may induce an increased chromosomal instability leading to clonal karyotypic evolution, which may mimic secondary chromosome aberrations in human Ph-positive ALL.

Animals↗
PubMed1996

Role for c-Abl tyrosine kinase in growth arrest response to DNA damage.

The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents, and its overexpression causes arrest in the G1 phase of the cell cycle by a mechanism dependent on the tumour-suppressor protein p53 (refs 2-4). Here we investigate the possible role of c-Abl in growth arrest induced by DNA damage. Transient transfection experiments using wild-type or inactivated c-Abl show that both induce expression of p21, an effector of p53, but only wild-type c-Abl downregulates the activity of the cyclin-dependent kinase Cdk2 and causes growth arrest. Exposure to ionizing radiation of cells that stably express active or inactive c-Abl is associated with induction of c-Abl/p53 complexes and p21 expression. However, cells expressing the dominant-negative c-Abl mutant and cells lacking the c-abl gene are impaired in their ability to downregulate Cdk2 or undergo G1 arrest in response to ionizing radiation. We also show that expression of c-Abl kinase in p21(-1-), but not in p53(-1-), cells results in downregulation of Cdk2. Our results suggest that c-Abl kinase contributes to the regulation of growth arrest induced by ionizing radiation by a p53-dependent, p21-independent mechanism.

CDC2-CDC28 Kinases↗
PubMed2002

In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells.

BACKGROUND: Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR-ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR-ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR-ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML. METHODS: The single agents and their combinations were studied for in vitro effect on proliferation of BCR-ABL positive cell lines KBM5 and KBM7 by 3(4,5-dimethylthiazol-2yl)-2,5 diphenyl-tetrazolium bromide assay and on primary patient-derived BCR-ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer-assisted analysis using the CalcuSyn software. RESULTS: STI571 consistently suppressed BCR-ABL positive cell proliferation with a dose-effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML-derived clonogenic cells in semisolid cultures. CONCLUSIONS: In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome-positive leukemias.

Antimetabolites, Antineoplastic↗
PubMed2004

A model of chromosome aberration induction and chronic myeloid leukaemia incidence at low doses.

Some chromosome aberration types, generally translocations, are correlated with specific cancers. An example is provided by chronic myeloid leukemia (CML) cells, most of which carry a translocation involving the ABL gene on chromosome 9 and the BCR gene on chromosome 22. The hypothesis of a causal relationship between CML and the chimeric protein product of the BCR-ABL translocation has recently received strong support. In this framework, a mechanistic model and Monte-Carlo code simulating radiation-induced chromosome aberrations in human lymphocytes will be presented. The current version of the model can predict dose-response curves for the main aberration types following acute irradiation with gamma rays and light ions of different energies. The model is based on the assumption that only clustered DNA lesions can lead to aberrations and that only lesion free ends in neighbouring chromosome territories can join and form exchanges. Such lesions are distributed within the cell nucleus according to the radiation track structure, i.e. randomly for low-LET radiation and along straight lines for high-LET light ions. Interphase chromosome territories are explicitly simulated and background aberrations are taken into account. Very good agreement was found with experimental data taken from the literature that provided a further validation of the model. As an application, yields of BCR-ABL translocations were calculated. Preliminary results led to a CML induction dose-response that is approximately quadratic below 0.1 Gy and essentially linear at higher doses up to 1 Gy. The numerical values obtained for the probability of CML induction are consistent with values obtained by other groups with different approaches.

Animals↗
PubMed1987

Unique forms of the abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL.

In the Philadelphia chromosome (Ph1) of chronic myelogenous leukemia (CML), the c-abl gene on chromosome 9 is translocated to bcr on chromosome 22. This results in the expression of a chimeric bcr-abl message that encodes the P210bcr-abl tyrosine kinase. The cells of 10% of acute lymphocytic leukemia patients (ALL) carry a cytogenetically similar Ph1 translocation. We report that Ph1-positive ALL cells express unique abl-derived tyrosine kinases of 185 and 180 kilodaltons that are distinct from the bcr-abl-derived P210 protein of CML. The appearance of the 185/180-kilodalton proteins correlates with the expression of a novel 6.5-kilobase messenger RNA. Thus, similar genetic translocations in two different leukemias result in the expression of distinct c-abl-derived products.

DNA, Neoplasm↗
PubMed1995

Treatment of Philadelphia-chromosome-positive human leukemia in SCID mouse model with herbimycin A, bcr-abl tyrosine kinase activity inhibitor.

The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin a, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph1-positive leukemia cell lines. Injection of Ph1-positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph1-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph1-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph1-positive leukemia. The disease that developed using the Ph1-positive leukemia cell line NALM-20 resembled human Ph1-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph1-positive leukemia.

Animals↗
PubMed1997

Stem cell kinetics.

Chronic myeloid leukaemia (CML) is a transplantable multi-lineage disease. In its initial chronic phase, the leukaemic clone exhibits a hierarchical structure that closely resembles normal haematopoiesis. Thus assays for in vitro colony-forming cells (CFC) and their more primitive precursors identified as long-term culture-initiating cells (LTC-IC) detect subsets of Ph+/BCR-ABL+ cells which cannot be readily distinguished from their normal counterparts. The use of these assays to examine the numbers, properties, genotype, distribution and regulation of primitive progenitors in patients' blood and marrow samples have revealed a number of unique and unexpected findings. These suggest that the indolent nature of the chronic phase of the disease may be explained by competing effects of the BCR-ABL gene product on the commitment to differentiate, control of cell cycle progression and apoptosis. As a result, the amplification of BCR-ABL+ stem cells is constrained but the expansion of their progeny is enhanced and, on the granulocyte pathway, this expansion proceeds unchecked to the stage of mature end cell production resulting in the leukaemic picture observed.

Animals↗
PubMed1995

Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents.

The product of the c-abl gene is a non-receptor tyrosine kinase that is localized to the nucleus and cytoplasm. The precise function of c-Abl is unknown. Here we show that ionizing radiation activates c-Abl. Similar results were obtained with the alkylating agents cis-platinum and mitomycin C. We also demonstrate that cells deficient in c-Abl fail to activate Jun kinase (JNK/SAP kinase) after ionizing radiation or alkylating agent exposure and that reconstitution of c-Abl in these cells restores that response. In contrast, the stress response to tumour-necrosis factor is stimulated by a c-Abl-independent mechanism. These findings indicate that c-abl is involved in the stress response to DNA-damaging agents.

3T3 Cells↗
PubMed2006

Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results.

The introduction in 1998 of imatinib mesylate (IM) revolutionized management of patients with chronic myeloid leukemia (CML) and the second generation of tyrosine kinase inhibitors may prove superior to IM. Real-time quantitative polymerase chain reaction (RQ-PCR) provides an accurate measure of the total leukemiacell mass and the degree to which BCR-ABL transcripts are reduced by therapy correlates with progression-free survival. Because a rising level of BCR-ABL is an early indication of loss of response and thus the need to reassess therapeutic strategy, regular molecular monitoring of individual patients is clearly desirable. Here we summarize the results of a consensus meeting that took place at the National Institutes of Health (NIH) in Bethesda in October 2005. We make suggestions for (1) harmonizing the differing methodologies for measuring BCR-ABL transcripts in patients with CML undergoing treatment and using a conversion factor whereby individual laboratories can express BCR-ABL transcript levels on an internationally agreed scale; (2) using serial RQ-PCR results rather than bone marrow cytogenetics or fluorescence in situ hybridization (FISH) for the BCR-ABL gene to monitor individual patients responding to treatment; and (3) detecting and reporting Philadelphia (Ph) chromosome-positive subpopulations bearing BCR-ABL kinase domain mutations. We recognize that our recommendations are provisional and will require revision as new evidence emerges.

Drug Monitoring↗
PubMed1984

The immI region of Salmonella phage P22. 1. Characterisation of the mutants P22 cir4-1, P22 cir5-1 and P22 cir6-1.

Salmonella phage mutants P22 cir4-1, P22 cir5-1 and P22 cir6-1 at 37 degrees C form more or less clear plaques. The mutants complement each other and clear mutations of the immC region (Prell et al. 1983). The mutants exhibit a strongly reduced frequency of lysogenisation, but form stable prophages. The low frequency of lysogenisation of P22 cir5-1 and of P22 cir6-1 is suppressed by an additional ant- mutation. Similarly, about 50% of turbid plaque revertants of both mutants carry ant- suppressor mutations. This suggests interference by the cir5-1 and cir6-1 mutations with the expression of gene ant. In contrast, the cir4-1 mutation seems not to interfere with ant expression, the latent periods of P22 cir4-1 and P22 cir5-1 are reduced and extended, respectively. The geneticly related Salmonella phage L carries a gene able to complement P22 cir4-1.

Genes, Viral↗
PubMed2002

Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336.

The development of chronic myeloid leukemia (CML) is dependent on the deregulated tyrosine kinase of the oncoprotein BCR-ABL. STI571 (imatinib mesylate), an abl tyrosine kinase inhibitor, has proven remarkably effective for the treatment of CML. However, resistance to STI571 because of enhanced expression or mutation of the BCR-ABL gene has been detected in patients. In the current study we show that the farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits the proliferation of STI571-resistant BCR-ABL-positive cell lines and hematopoietic colony formation from peripheral blood samples of STI571-resistant patients with CML. Moreover, SCH66336 enhances STI571-induced apoptosis in STI571-sensitive cells and, in patients with STI571 resistance from gene amplification, cooperates with STI571 to induce apoptosis. Our data provide a rationale for combination clinical trials of STI571 and SCH66336 in CML patients and suggest that combination therapy may be effective in patients with STI571 resistance.

Alkyl and Aryl Transferases↗
PubMed1999

Abl expression, tumour grade, and apoptosis in chondrosarcoma.

AIMS: To determine whether Abl immunoreactivity correlates with grade and cell kinetics (apoptosis and mitosis) in chondrosarcoma. METHODS: Sections from 16 chondrosarcomas were stained immunohistochemically using a polyclonal antibody to the c-Abl/Bcr-Abl oncoprotein. Apoptotic indices and mitotic indices were assessed in all tumours. Sections from 24 paraffin wax blocks of human fetal rib (gestational ages, 15-42 weeks) were also stained to determine whether the Abl protein is synthesised consistently throughout endochondral ossification. RESULTS: Abl staining in immature fetal rib chondrocytes at all stages of development was predominantly nuclear, and 70% of cells showed moderate to strong staining. Abl immunoreactivity was minimal or absent in hypertrophic chondrocytes about to undergo apoptosis at the growth plate. There was strong Abl staining in grade 1 and grade 2 chondrosarcomas but staining was greatly reduced or absent in grade 3 chondrosarcomas. There was a very significant linear correlation between apoptotic index (mean, 0.68%; range, 0-3.2%) and mitotic index (mean, 0.23%; range, 0-0.9%), and both indices were significantly lower in grade 1 than in grade 2 and grade 3 chondrosarcomas. CONCLUSIONS: These data suggest that abl gene expression is associated with differentiation and apoptosis inhibition in fetal and neoplastic chondrocytes. However, these putative effects cannot be ascribed solely to the Abl protein, because several additional factors contribute to the regulation of both differentiation and apoptosis.

Apoptosis↗