Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Genes, abl”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,171 records · Page 65Linked to original sources
PubMed1990

Bcr/abl recombinant DNA analysis versus karyotype in the diagnosis and therapeutic monitoring of chronic myeloid leukemia.

Karyotype and bcr/abl recombinant DNA analyses are two means of detecting the chromosomal aberration in chronic myeloid leukemia. The authors compared these two methods in a retrospective study of 36 patients with CML in which they found the bcr/abl DNA recombinant event in 100% (29 of 29) of those patients who had the Philadelphia chromosome. To achieve this sensitivity, a battery of two bcr probes and three restriction enzymes is necessary. The authors propose a sequential algorithm for efficient use of these probes and enzymes. In 76% of the patients, bcr/abl rearrangement can be detected with a Bgl II digest and a 3' commercial probe. An additional 21% of patients can be detected by a second assay in which the same membrane is rehybridized to a 3' and 5' combination bcr probe. One patient (3%) required an additional restriction enzyme digest with BamH I to detect the recombinant event by the same 3' probe. Karyotype analysis is used to determine cytogenetic remission in patients with CML under therapy. The authors studied the use of DNA analysis by the Southern blot technique to detect a decrease in the relative number of leukemic cells. By dilution studies and densitometric scanning of autoradiographs, the authors were able to detect a 15% decrease in the relative number of cells having the bcr/abl recombinant event. The authors report the preliminary results of three patients in whom they compared the karyotype and recombinant DNA analysis at multiple time points in their clinical course. In conclusion, the bcr/abl recombinant DNA analysis is superior to karyotype for the diagnosis of CML and can be used for monitoring treated patients.

Adolescent↗
PubMed1998

Chronic myeloid leukemia.

Progress has been made in understanding BCR-ABL-positive leukemias. A new transcript (p230BCR-ABL) has been characterized that is associated with Ph-positive chronic neutrophilic leukemia. The ATM protein appears to be a regulator of ABL activity in response to irradiation damage. Pathways linking BCR-ABL to the BCL-2 family of proteins may be active in Philadelphia-positive cells and inhibit apoptosis. The 62-kD protein constitutively phosphorylated in chronic myeloid leukemia progenitors has been cloned. Ph-negative long-term culture-initiating cells are detectable in many chronic myeloid leukemia patients. The combination of interferon alfa and cytarabine appears to be superior to interferon alfa alone. Autografting with in vivo-purged stem cells may induce prolonged remissions. Specific inhibitors of the BCR-ABL tyrosine kinase are becoming available.

Antineoplastic Agents↗
PubMed1991

Single rol Genes from the Agrobacterium rhizogenes T(L)-DNA Alter Some of the Cellular Responses to Auxin in Nicotiana tabacum.

Two kinds of cellular responses to auxin, the hyperpolarization of protoplasts and the division of protoplast-derived cells, were compared in Nicotiana tabacum plants transformed by different T-DNA fragments of Agrobacterium rhizogenes strain A4. Using transmembrane potential difference measurements to characterize hormonal sensitivity of mesophyll protoplasts, we found a 30-fold increase in sensitivity to auxin in protoplasts transformed by the whole Ri A4 T-DNA. Furthermore, the rol genes of the Ri A4 T(L)-DNA, together or as single genes, were able to increase the sensitivity to auxin by factors up to 10(4). The different effects of the single rol genes on the sensitivity of mesophyll protoplasts to auxin, rolB being the most powerful, were consistent with their respective rhizogenic effects on leaf fragments (A Spena, T Schmülling, C Koncz, J Schell [1987] EMBO J 6: 3891-3899). No difference was seen concerning the effects of auxin on division of cells derived from normal or transformed protoplasts. These results suggest that only some cellular responses to auxin could be selectively altered by rol genes. They also show that rol-transformed tobaccos can be a model system to study auxin action in plants.

Journal Article↗
PubMed2002

High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance.

Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph(+) ALL) and imatinib resistance (defined as loss of established hematologic response), but they were found in only 1 of 10 patients with CML with imatinib refractoriness (failure to achieve cytogenetic response). In 10 of 10 patients for whom samples were available, the mutation was not detected before the initiation of imatinib therapy. Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255K, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients. Screening may allow intervention before relapse by identifying emerging mutations with defined impacts on imatinib binding. Certain mutations may respond to higher doses of imatinib, whereas other mutations may mandate switching to another therapeutic strategy.

Adenosine Triphosphate↗
PubMed2005

Bcr-Abl regulates osteopontin transcription via Ras, PI-3K, aPKC, Raf-1, and MEK.

Chronic myeloid leukemia (CML) is caused by the constitutively active Bcr-Abl tyrosine kinase. This fusion protein is generated by the Philadelphia translocation t(9;22). CML is a progressive condition that invariably advances from a drug-sensitive to a drug-resistant, aggressive, acute leukemia. The mechanisms responsible for this progression are largely unknown; however, in many cases, progression is accompanied by an increase in Bcr-Abl expression. Osteopontin (OPN) expression has been shown to be involved in the progression and increased aggression and invasiveness of many solid tumors. Here, we demonstrate that OPN expression is induced in a model of leukemia, and we describe the identification of specific signaling pathways required for the induction of OPN expression by p210 Bcr-Abl. We have determined that high levels of Bcr-Abl activate a signaling cascade involving the sequential activation of Ras, phosphatidylinositol-3 kinase, atypical protein kinase C, Raf-1, and mitogen-activated protein kinase kinase, leading to the ultimate expression of OPN. Our results suggest that these molecules represent a single pathway and also that there is no redundancy in this pathway, as inhibition of any individual component results in a block in the induction of OPN. The data presented here define for the first time the ability of Bcr-Abl to stimulate the expression of OPN and also identify the signaling pathway involved. This may not only prove important in understanding the mechanisms of progression of CML but also highlights a pathway that may prove significant in many other cases of oncogenesis, where OPN expression is implicated.

Animals↗
PubMed2002

Functional expression of chitinase and chitosanase, and their effects on morphologies in the yeast Schizosaccharomyces pombe.

The chitinase A (chiA) gene from Enterobacter sp. G-1 and the chitosanase A (choA) gene from Matsuebacter chitosanotabidus 3001 were expressed separately and simultaneously in the yeast Schizosaccharomyces pombe. The chiA gene was placed under the transcriptional control of the nmt1 promoter with the glutathione S transferase (GST), and the choA gene was expressed by the human cytomegalovirus (hCMV) promoter with the P factor secretion signal (P3). The expressed proteins of ChoA and GST-ChiA were enzymatical active and were detected as 34-kDa and 80-kDa, respectively, by Western blot analysis. The transformant that expressed the choA gene was able to secrete ChoA efficiently into the culture medium with the specific activity of 102.36 U/mg protein. When the chiA gene was expressed in S. pombe, yeast cells grew slowly and cells became elongated, but when the choA gene was expressed, cells became swollen. Expression of both the chiA and the choA genes resulted in elongated and fat cells.

Blotting, Western↗
PubMed2002

Philadelphia chromosome-positive chronic myeloid leukemia expressing p190(BCR-ABL).

We describe a case of Philadelphia chromosome-positive chronic myeloid leukemia (Ph-positive CML) expressing p190(BCR-ABL). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of bone marrow cells showed a 472-bp band using primers specific for the p190(BCR-ABL) but not p210(BCR-ABL) transcript. Sequencing analysis revealed that the PCR product was derived from the fusion between BCR exon e1 and ABL exon a2 (e1a2). CML expressing p190(BCR-ABL) is relatively rare. In a review of the literature, it may be grouped into 2 categories; approximately half of the patients exhibited prominent monocytosis and intermediate hematological phenotype between CML and chronic myelomonocytic leukemia, and the remaining patients showed no monocytosis.

Adenocarcinoma↗
PubMed1994

[Molecular basis of chronic granulocytic leukemia: from test-tube to patient].

BCR/ABL tyrosine kinases are encoded by hybrid oncogene bcr/abl which is a result of t(9;22) reciprocal translocation. Bcr/abl oncogene is located on Philadelphia chromosome which is detectable in hematopoietic cells of more than 95% of patients with chronic myelogenous leukemia, and in some cases of acute lymphocytic leukemia (20-35%) and acute myeloblastic leukemia (5%). Because BCR/ABL tyrosine kinase is localized in the cytoplasm, cooperation with other cytoplasmic and nuclear molecules is necessary for the induction of leukemia. Identification of the molecular mechanisms involved in transduction of the oncogenic signal is likely to be useful in elucidating the molecular mechanisms of leukemogenesis and may eventually lead to the identification of novel targets for antileukemia therapy. One of the possible treatment--inhibition of bcr/abl oncogene expression by antisense strategy--is described below.

Animals↗
PubMed1996

Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice.

The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis (CML-BC) primary cells were treated in vitro with bcr-abl and c-myc antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.

Animals↗
PubMed1995

Abnormal chromatin clumping in granulocytes in a case of Ph1-negative, BCR-ABL rearrangement positive, haematologically atypical chronic myeloid leukaemia (CML).

In the present study, we report the case of a patient displaying an abnormal chromatin clumping (ACC) syndrome, a rare disease which shares features with both myeloproliferative and myelodysplastic disorders. Although various non specific cytogenetic abnormalities have been observed in ACC, the presence of a Ph1 chromosome has not been reported. In our patient, despite a lack of Ph1, PCR analysis of blood and bone marrow samples revealed a BCR-ABL rearrangement. These results indicate that at least some cases of ACC syndrome could represent a form of Ph1-negative chronic myeloid leukaemia.

Aged↗
PubMed1998

2',5'-Oligoadenylate-antisense chimeras cause RNase L to selectively degrade bcr/abl mRNA in chronic myelogenous leukemia cells.

We report an RNA targeting strategy, which selectively degrades bcr/abl mRNA in chronic myelogenous leukemia (CML) cells. A 2', 5'-tetraadenylate activator (2-5A) of RNase L was chemically linked to oligonucleotide antisense directed against either the fusion site or against the translation start sequence in bcr/abl mRNA. Selective degradation of the targeted RNA sequences was demonstrated in assays with purified RNase L and decreases of p210(bcr/abl) kinase activity levels were obtained in the CML cell line, K562. Furthermore, the 2-5A-antisense chimeras suppressed growth of K562, while having substantially reduced effects on the promyelocytic leukemia cell line, HL60. Findings were extended to primary CML cells isolated from bone marrow of patients. The 2-5A-antisense treatments both suppressed proliferation of the leukemia cells and selectively depleted levels of bcr/abl mRNA without affecting levels of beta-actin mRNA, determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The specificity of this approach was further shown with control oligonucleotides, such as chimeras containing an inactive dimeric form of 2-5A, antisense lacking 2-5A, or chimeras with altered sequences including several mismatched nucleotides. The control oligonucleotides had either reduced or no effect on CML cell growth and bcr/abl mRNA levels. These findings show that CML cell growth can be selectively suppressed by targeting bcr/abl mRNA with 2-5A-antisense for decay by RNase L and suggest that these compounds should be further explored for their potential as ex vivo purging agents of autologous hematopoietic stem cell transplants from CML patients.

Adenine Nucleotides↗
PubMed2002

Relationship of the BCR gene breakpoint and the type of BCR/ABL transcript to clinical course, prognostic indexes and survival in patients with chronic myeloid leukemia.

BACKGROUND: Chronic myeloid leukemia is characterized by the presence of the Philadelphia chromosome. At the molecular level a fusion of part of the ABL and BCR genes is observed. The breakpoint locations in the BCR gene fall between exons b2a2 or b3a2 (5' and 3', respectively). Depending on the BCR gene breakpoint two types of mRNA are created. Differences in the types of transcripts and/or the breakpoint site may have an influence on the clinical course of the disease. This prompted the present author to separate subtypes of chronic myeloid leukemia on the molecular level. MATERIAL/METHODS: 71 patients diagnosed with chronic myeloid leukemia in the chronic phase were enrolled in the study. In 61 patients the type of BCR/ABL transcript was determined, and in 27 patients BCR breakpoints were established. Possible correlations between the clinical course, prognostic indexes, survival and the type of transcript and breakpoint were examined. RESULTS: No correlation between the clinical course, prognostic index, or survival was observed in patients with 5' and 3' breakpoints. The patients with b3a2 transcript experienced longer survival than the patients expressing b2a2 transcript. However, no significant differences were observed in the duration of the chronic phase between the two groups. CONCLUSIONS: The type of BCR gene breakpoint seems to have no prognostic value in patients with chronic myeloid leukemia. The longer survival of patients expressing the b3a2 transcript may be caused by the less aggressive course of the accelerated or blastic phase.

Adolescent↗
PubMed2004

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders.

Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.

Antineoplastic Agents↗
PubMed2004

[Clinical efficacy and side effects of STI571 in treatment of patients with chronic myeloid leukemia].

BACKGROUND & OBJECTIVE: The aberrant regulation of the protein tyrosine kinase (PTK) activity of P210(BCR-ABL), which is the protein product of Bcr-Abl fusion gene leads to the pathogenesis of chronic myeloid leukemia (CML). Though STI571 can inhibit specifically the PTK activity of P210(Bcr-Abl) and greatly improve the clinic curative effect on CML in chronic phase, its effect on CML in accelerated phase and blast crisis is not clear. In this article, we attempted to analyze the clinic efficacy and side effect of STI571 treatment on CML patients in different phase. In addition, we analyzed the potential mechanism of STI571 resistance in accelerated/blast crisis CML with genetic methods. METHODS: A total of 22 cases of CML, 14 cases male and 8 female, 6 cases in chronic phase and 16 cases in accelerated/blast crisis phase, were treated with STI571. According to the efficacy standard, the hematological and cytogenetic response of 22 cases CML were analyzed, by determining the positive rate of Ph chromosome in bone marrow from the patients treated with STI571 for 3 months. Furthermore, the karyotype evolution of those patients showing STI571 resistance was analyzed. At the same time, the side effects and adverse events of STI571 treatment were evaluated. RESULTS: 6/6(100%) cases of CML patients in chronic phase acquired hematological CR and cytogenetic response. 4/16(25%) cases in accelerated phase or blast crisis acquired hematological CR and 8/16(50%) cases acquired cytogenetic response. 3 CML patients in blast crisis showed secondary STI571 resistance. The karyotype analysis shows 2 with 2 Ph chromosome and other additional abnormality. I/II grade non-hematological toxicity was observed in all the patients, including edema (77.3%), side effects of digestive system (36.4%) and myalgia (22.7%) et al. Severe hematological toxicities includes:(1)III/IV grade neutropenia (9 cases):1/6 cases of CML patients in chronic phase, 8/16 cases in accelerated phase or blast crisis; (2)III/IV grade thrombocytopenia (6 cases): 6/16 cases in accelerated phase or blast crisis. The percentage of III/IV grade neutropenia/thrombocytopenia in chronic phase and accelerated/blast crisis phase was compared and no significant statistical difference was observed. CONCLUSIONS: Hematological and cytogenetic responses of different degrees can be acquired in CML-CP and CML-AP/BC patients treated with STI571 and showing statistic difference. STI571 improves the clinic curative effect greatly on CML in chronic phase. CML patients in blast crisis have secondary STI571 resistance with novel 2 Ph chromosome and other additional abnormality, it furnishes the evidence of the gene changes. The slightness of non-hematological toxicity of STI571 in the treatment of chronic myeloid leukemia suggests this drug is relatively safe. Severe hematological toxicities, such as III/IV neutropenia and thrombocytopenia, are more common in accelerated/blast crisis than in chronic phase.

Adolescent↗