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At least 595 records · Page 33Linked to original sources
PubMed2006

Characterization of p87C3G, a novel, truncated C3G isoform that is overexpressed in chronic myeloid leukemia and interacts with Bcr-Abl.

A novel C3G isoform, designated p87C3G, lacking the most amino terminal region of the cognate protein has been found to be overexpressed in two CML cell lines, K562 and Boff 210, both expressing Bcr-Abl p210. p87C3G expression is also highly augmented in patients diagnosed with chronic myeloid leukemia (CML) Ph+, in comparison with healthy individuals, and returns to basal levels after treatment with STI571. p87C3G co-immunoprecipitates with both CrkL and Bcr-Abl in CML cell lines and co-immunoprecipitation between p87C3G and Bcr-Abl was also detected in primary cells from CML patients. These interactions have been confirmed by in vitro pull down experiments. The interaction between p87C3G and Bcr-Abl involves the SH3-binding domain of p87C3G and the SH3 domain of Abl and depends mostly on the first polyproline region of p87C3G. Furthermore, we also demonstrated that p87C3G is phosphorylated in vitro by a Bcr-Abl-dependent mechanism. These results indicate that p87C3G overexpression is linked to CML phenotype and that p87C3G may exert productive functional interactions with Bcr-Abl signaling components suggesting the implication of this C3G isoform in the pathogenesis of chronic myeloid leukemia.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Detection of the Mbcr/abl translocation in chronic myeloid leukemia by fluorescence in situ hybridization: comparison with conventional cytogenetics and implications for minimal residual disease detection.

The correlation between the detection of the Philadelphia chromosome by conventional cytogenetics and the identification of Mbcr/abl translocation by fluorescence in situ hybridization (FISH) in both metaphase and interphase cells is prospectively analyzed in a group of 21 chronic myeloid leukemia (CML) patients. To gain insight into the sensitivity and specificity of the detection of the bcr/abl translocation by FISH, a group of 10 healthy volunteers was also studied. Our results show that for the detection of bcr/abl translocation in CML patients, FISH is more sensitive than conventional cytogenetics because it detects significantly higher proportions of cells carrying the translocation both in metaphase (P < .0002) and interphase nuclei (P < .003). Moreover, in the metaphases of the controls analyzed, no bcr/abl+ chromosome was detected that makes the colocalization of bcr and abl signals in the CML patients highly specific. Conversely, in control interphase nuclei, a small proportion of cells (ranging between 0% and 3%, mean value of 1.7% +/- 0.9%) displaying colocalization of both signals is usually detected. This limits, at least for the moment, the routine use of FISH for the detection of minimal residual disease in CML patients at levels lower than 10(-1).

Adult↗
PubMed1984

Altered transcription of an oncogene in chronic myeloid leukaemia.

The oncogene abl, which resides on chromosome 9, is translocated to chromosome 22 as part of the Philadelphia (Ph1) chromosome. Leukaemic cells from 5 of 6 patients with chronic myelogenous leukaemia (CML) and the Ph1 chromosome were found to contain a new 8 kb abl RNA transcript. This finding raises the possibility that the abl oncogene is directly involved in the development of CML. It is suggested that the abl gene's expression is altered by the DNA rearrangement in the translocation.

Adult↗
PubMed2000

Extramedullary blast crisis in a patient with chronic myelogenous leukemia in complete cytogenetic and molecular remission on interferon-alpha therapy.

We report the previously undescribed occurrence of extramedullary blast crisis in a patient with chronic myelogenous leukemia in complete cytogenetic and molecular remission on interferon-alpha. Development of bilateral testicular swelling prompted a biopsy showing stromal infiltration with CD20 and TdT positive immature cells. On repeated examinations, the bone marrow remained BCR/ABL negative by RT-PCR analysis. However, the cerebrospinal fluid (CSF) contained atypical lymphocytes positive for the P210 BCR-ABL product. Following treatment with testicular irradiation, intrathecal methotrexate, systemic chemotherapy and an unrelated donor transplant, the patient showed no evidence of disease until 9 months post-transplant, when he relapsed in lymphoid blast crisis in both bone marrow and CSF.

Adult↗
PubMed1998

Detection of BCR-ABL transcripts in acute lymphoblastic leukemia in Indian patients.

Thirty-three patients with acute lymphoblastic leukemia (ALL) from India were studied for the presence of BCR-ABL chimeric transcripts, by a seminested cDNA-PCR. We report the presence of BCR-ABL chimeric transcripts in 4/17 (24%) children (under 15 years) and 3/16 (19%) adults (15-50 years). This is in sharp contrast to the published literature from the West where the presence of BCR-ABL has been reported in only 2-5% children and 35% adults. Whether the presence of BCR-ABL fusion mRNA, which is generally an attribute of ALL in adults and of poorer prognosis, may contribute to chemo-incurability in young Indian patients, remains to be seen, as a larger number of patients are studied for treatment outcome and survival on uniform therapy protocols.

Adolescent↗
PubMed1997

Philadelphia chromosome in chronic myelogenous leukemia: confirmation of cytogenetic diagnosis in Ph positive and negative cases by fluorescence in situ hybridization.

In this study, patients with Philadelphia (Ph) negative and positive chronic myelogenous leukemia (CML) were analyzed by unicolor- and dual color- (DC) fluorescence in situ hybridization (FISH) using abl and bcr cosmid probes. Unicolor- and DC-FISH analysis revealed a BCR-ABL fusion in a Ph-negative patient. DC-FISH to interphase nuclei revealed the BCR-ABL fusion, even though no metaphases were available for metaphase-FISH and conventional cytogenetic analysis. In the remaining cases, the findings of FISH were in agreement with the cytogenetic results.

DNA, Neoplasm↗
PubMed1999

BCR/ABL translocation in adult acute lymphoblastic leukemia: a comparison of conventional and interphase cytogenetic studies.

Twenty-four adult Chinese patients with de novo acute lymphoblastic leukemia (ALL) were studied for the BCR/ABL translocation using both conventional cytogenetics and fluorescence in situ hybridization (FISH). Eight (33%) patients had the translocation as shown by FISH and all were B-lineage ALL (8/19, 42%). Conventional cytogenetics revealed a t(9;22)(q34;q11) in six of them, but was either unsuccessful, or not done in the other two. Seven of the eight positive cases (88%) showed a breakpoint at the minor breakpoint cluster region (m-BCR), which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). To conclude, the frequency of BCR/ABL translocation in Chinese patients with de novo ALL is comparable to patients in the Western hemisphere, in contrast to a previous report. The predominance of m-BCR/ABL fusion among these Chinese patients with BCR/ABL translocation is also similar to patients in the Western population. Fluorescence in situ hybridization is a sensitive, specific and relatively simple technique for demonstrating this important unfavorable prognostic marker in ALL, even in a routine service laboratory setting.

Adult↗
PubMed2003

Molecular targets in acute myelogenous leukemia.

Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, most patients will either die of relapse or die from the complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed. Recently, a small molecular inhibitor (STI571 or Gleevec) that targets the BCR-ABL gene was found to have a dramatic clinical effect in patients with chronic myelogenous leukemia (CML). These results have encouraged investigators to search for additional small molecular inhibitors and other targeted therapies that may be applicable to other forms of leukemia. In this review, we examine some of the signaling pathways that are aberrantly regulated in AML, focusing on the tyrosine kinase/RAS/MAP kinase and JAK/STAT pathways. After reviewing these two pathways, we explore some of the targeted therapies directed at these pathways that are under development for AML, many of which are already in clinical trials.

Enzyme Inhibitors↗
PubMed1999

Pathological relevance of epithelial and mesenchymal phenotype plasticity.

Epithelium and mesenchyme, two tissue types virtually found in every organ, are endowed with fundamentally different functional properties. Active motility, a capability that is limited to the mesenchymal repertoire, is the principal characteristic that distinguishes them. During embryonic development, conversions from epithelium to mesenchyme and from mesenchyme to epithelium normally occur, allowing morphogenetic processes and tissue remodelling to take place. However, there is now increasing evidence that the modulation between the epithelial and the mesenchymal phenotypes is not limited to embryonic life. Indeed, the pathogenesis of some adult diseases seems to implicate an inappropriate activation of this change. On the other hand, failure of normally occurring embryonic epithelial-mesenchymal interconversions could result in the development of some pathologies. It is now possible to study some molecular events underlying these phenotype transitions, since several biological agents implicated in the epithelial-mesenchymal interconversion, such as growth factors, extracellular matrix components and their receptors, transcription factors and oncogenes have been identified. The malignant potential of some oncogenes seems to express itself through the disruption of the mechanisms involved in the maintenance of the epithelial phenotype while, on the other hand, some observations suggest the existence of regulatory genes able to counteract the action of oncogenes by restoring epithelial characteristics. Therefore, the manipulation of the tissue phenotype could represent a novel strategy for the prevention and treatment of diseases in the future.

Bone Neoplasms↗
PubMed2003

Targeting tumor cells.

Several recent scientific and technical developments have made it possible to postulate the use of the 'magic bullet' concept; that is, the identification of specific antigens present on tumor cells that can be targeted either by therapeutic antibodies or by small molecules. The use of monoclonal antibodies in cancer, in particular, has moved beyond the proof-of-concept stage, and many such antibodies are presently being tested in the clinic. Several antibodies have been successfully developed and are now in use against various cancers, and we can expect many more to become available in the next few years. The use and development of these new therapeutics represent significant opportunities but also new challenges.

Animals↗
PubMed1993

Abl tyrosine kinase in signal transduction and cell-cycle regulation.

Although the biological function of the c-Abl tyrosine kinase remains unsolved, potentially productive avenues towards the elucidation of that function have been identified by recent progress. An F-actin binding and a sequence-specific DNA-binding domain have been discovered in c-Abl, and DNA binding has been shown to be cell-cycle regulated. Deletion of those two domains in the mouse c-Abl results in a loss of biological function despite the production of an active tyrosine kinase. These findings suggest a role for c-Abl in the regulation of processes occurring on F-actin and on specific DNA elements.

Amino Acid Sequence↗
PubMed2001

Immune diversity and genomic stability: opposite goals but similar paths.

DNA damage response mechanisms serve to protect cells from exogenous and endogenous DNA damaging agents with the aim of maintaining genomic stability. In contrast, the generation of an efficient immune response requires the creation of a repertoire of distinct immunoglobulin and T cell receptor genes able to recognise the huge array of antigens that may be encountered in a lifetime. Surprisingly, cells have exploited the same mechanisms used to maintain genomic integrity to create genetic diversity during immune development. Here, we review the damage response mechanisms operating on DNA double strand breaks and their function during development of the immune response. We discuss disorders that are associated with immunodeficiency and defective responses to the presence of DNA double strand breaks.

Animals↗
PubMed1997

Activation of hematopoietic growth factor signal transduction pathways by the human oncogene BCR/ABL.

BCR/ABL is a human chimeric oncogene that causes chronic myelogenous leukemia (CML). The BCR/ABL oncogene is generated from the Philadelphia chromosome (Ph) translocation, t(9;22)(q34;q11), and creates a constitutively active tyrosine kinase. There is clonal expansion of hematopoietic stem cells of several different lineages in CML. CML patients in stable phase usually have high white blood counts and immature cells of granulocytic lineages. Stable phase CML evolves to a more aggressive phase typically within 3.5-5 years, where differentiation is blocked and acute leukemia ensues. The transition of CML stable phase to blast phase is reflected in the loss of growth factor requirement of CML cells and correlates with additional cytogenetic alterations. Some biological effects reported in primary CML cells include reduced apoptosis and altered adhesion to fibronectin; however, the cells are dependent on hematopoietic growth factors. On a molecular level, the BCR/ABL translocation is well characterized. However, the actual mechanism of transformation by the BCR/ABL oncogene of hematopoietic cells is largely unknown. Enhancement of the c-ABL tyrosine kinase activity in BCR/ABL appears to be crucial for transformation. This tyrosine kinase activity leads to activation of several signal transduction pathways that are also utilized by hematopoietic growth factors, including steel factor, thrombopoietin, interleukin-3, and granulocyte/macrophage-colony stimulating factor. In several model systems, BCR/ABL has overlapping biological effects with hematopoietic growth factors, and transformation of hematopoietic growth factor-dependent cell lines leads to growth factor independence. In this review, we will describe the molecular and biological abnormalities in CML and several signal transduction mechanisms utilized by BCR/ABL as compared to hematopoietic growth factors.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Antisense therapy for cancer--the time of truth.

The recent acceleration in the identification and characterisation of new molecular targets for cancer and the limited effectiveness of conventional treatment strategies has focused considerable interest on the development of new types of anticancer agents. These new drugs are hoped to be highly specific for malignant cells with a favorable side-effect profile due to well-defined mechanisms of action. Antisense oligonucleotides are one such class of new agent--they are short, synthetic stretches of DNA which hybridise with specific mRNA strands that correspond to target genes. By binding to the mRNA, the antisense oligonucleotides prevent the sequence of the target gene being converted into a protein, thereby blocking the action of the gene. Several genes known to be important in the regulation of apoptosis, cell growth, metastasis, and angiogenesis, have been validated as molecular targets for antisense therapy. Furthermore, new targets are rapidly being uncovered through coordinated functional genomics and proteomics initiatives. Phosphorothioate oligonucleotides are the current gold standard for antisense therapy; they have acceptable physical and chemical properties and show reasonable resistance to nucleases. Recently, new generations of these phosphorothioate oligonucleotides that contain 2'-modified nucleoside building blocks to enhance RNA binding affinity and decrease indirect toxic effects have been developed. Antisense therapeutics are, after decades of difficulties, finally close to fulfilling their promise in the clinic.

Apoptosis↗
PubMed2004

Efficient silencing of bcr/abl oncogene by single- and double-stranded siRNAs targeted against b2a2 transcripts.

In this work, double- and single-stranded small-interference RNAs (siRNAs) were designed to knock down the bcr/abl oncogene in leukaemia KYO-1 cells. The siRNA molecules were targeted against two distinct sites encompassing the b2a2 junction of the bcr/abl transcripts. The siRNAs were able to reduce the levels of both bcr/abl mRNA and protein p210(BCR/ABL). Conversely, control siRNAs bearing 3 or 4 base-pair substitutions did not produce any inhibitory effect. The designed siRNAs were also found to be active in KCl22 cells, which harbor the b2a2 junction, but not in K562 cells, which, by contrast, harbor the b3a2 junction. The anti-b2a2 siRNAs promoted biological effects on KYO-1 cells, because the bcr/abl suppression resulted in the inhibition of cell growth and colony formation in agar and activation of apoptosis and upregulation of the cell-cycle inhibitor p27 protein. The bioactivity of the designed siRNAs is discussed in terms of internal stability of the RNA duplexes. Our data suggest that siRNAs can be considered strong tools for functional analysis of bcr/abl and for developing molecular therapeutic approaches to leukaemia.

Base Sequence↗
PubMed2002

Enrichment of normal progenitors in counter-flow centrifugal elutriation (CCE) fractions of fresh chronic myeloid leukemia leukapheresis products.

OBJECTIVES: The aim of this study was to assess the suitability of a technique based on counter-flow centrifugal elutriation (CCE), which should allow one to enrich chronic myeloid leukemia (CML) patients' unstimulated native leukapheresis product (nLP) in CD34+ HLADR- cells and BCR-ABL negative cells. METHODS: Six newly diagnosed CML patients were subjected to leukapheresis, and the products were subfractionated with the use of CCE. nLP and all fractions were studied for the presence of CD34+ cells and a proportion of BCR-ABL fluorescence in situ hybridization (FISH)+ cells. RESULTS: CCE fractions with a high flow rate contained the highest proportion of CD34+ cells [mean (SEM) 6.89% (3.88)]. However, CD34+ cells present in low-rate CCE fractions showed a higher proportion of HLADR-[49.6% (13.5 in 70 mL min-1) and 21.5% (11.6 in 110 mL min-1)] than those in 170 mL min-1[3.2% (2.5)] and "rotor off" [3.4% (1.9)]. This was associated with lower proportions of BCR-ABL FISH+[8.1% (4.8) and 1.9 (1.7)] and smaller BCR-ABL to ABL transcript ratios [0.58 (17) and 0.26 (0.08) in 70 and 110 mL min-1] fractions as compared to 140 and 170 mL min-1 fractions [21.6% (5.2) and 31.6% (15.3) for BCR-ABL FISH+ cells and 0.75 (0.16) and 0.90 (0.24) for BCR-ABL/ABL]. Fractions with the lowest proportions of BCR-ABL-positive cells and the lowest BCR-ABL/ABL transcript ratios (110 mL min-1) contained from 1.3 x 106 to 82.7 x 106 (median: 3.97 x 106) CD34+ cells. CONCLUSIONS: In the present study we have shown that CCE may be used effectively to obtain nLP fractions enriched in normal hematopoietic progenitors.

Adult↗
PubMed2000

Quantification of BCR-ABL transcripts in CML patients in cytogenetic remission after interferon-alpha-based therapy.

We measured using a competitive quantitative polymerase chain reaction-capillary electrophoresis (PCR-CE)-based assay, the levels of bcr-abl transcripts in 44 patients with chronic myeloid leukemia (CML) after interferon-alpha (IFN-alpha) therapy, who achieved a major (10 patients, MCR group) or complete (34 patients, CCR group) cytogenetic response. All 34 CCR patients had molecular evidence of residual disease detected in bone marrow samples at the time of best karyotypic response. The median number of bcr-abl transcripts of 34 evaluable patients in the CCR group at the time of complete cytogenetic remission was 4/microg RNA (range 3-4600), while the median number of bcr-abl transcripts of 10 patients in the MCR group at the time of best cytogenetic response was 4490/microg RNA (range 600-23 900) (P = 0.000024). In nine CCR and five MCR patients we were able to quantify the amount of bcr-abl transcript both at diagnosis and after interferon therapy: no statistical difference (P = 0.18) was found between the two groups at diagnosis (median bcr-abl transcripts/microg RNA was 30 000 vs. 39 650, respectively). During IFN-alpha therapy, the two groups were evaluable at the time of major karyotypic conversion: at this point, there was a statistical difference of expression of bcr-abl transcript between the CCR group (17 patients) (median 2700; range 76-40 000) and the MCR group (10 patients) (median 4490; range 600-23 900), respectively (P = 0.046). No differences of bcr-abl amount of transcript were found in patients with CCR obtained either by IFN-alpha therapy alone (20 patients) vs. IFN-alpha plus ABMT (13 patients) (P = 0.47). We firstly demonstrated that although the CCR and MCR groups were clinically, cytogenetically and molecularly indistinguishable at diagnosis, the two groups could be recognized successfully during interferon therapy based on the level of bcr-abl transcript.

Adolescent↗
PubMed1997

The BCR/ABL oncogene alters interaction of the adapter proteins CRKL and CRK with cellular proteins.

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML). In primary leukemic neutrophils from patients with CML, the major tyrosine phosphorylated protein is CRKL, an SH2-SH3-SH3 adapter protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene. In cell lines transformed by BCR/ABL, CRKL was tyrosine phosphorylated, while CRK was not. We looked for changes in CRK- and CRKL-binding proteins in Ba/F3 hematopoietic cell lines which were transformed by BCR/ABL. Anti-CRK II or anti-CRKL immunoprecipitates were probed by far Western blotting with CRK II- or CRKL-GST fusion proteins to display CRK- and CRKL-coprecipitating proteins. There was a striking qualitative difference in the proteins coprecipitating with CRKL and CRK II. In untransformed cells, three major proteins coprecipitated with CRKL, identified as C3G, SOS and c-ABL. Each of these proteins was found to interact with the CRKL-SH3 domains, but not the SH2 domain. After BCR/ABL transformation, the CRKL SH3-domain binding proteins did not change, with the exception that BCR/ABL now coprecipitated with CRKL. Compared to CRKL, very few proteins coprecipitated with CRK II in untransformed, quiescent cells. After BCR/ABL transformation, both the CRKL- and CRK-SH2 domains bound to a new complex of proteins of approximate molecular weight 105-120 kDa. The major protein in this complex was identified as p120CBL. Thus, in these hematopoietic cell lines, CRKL is involved to a greater extent than CRK II in normal signaling pathways that involve c-ABL, C3G and SOS. In BCR/ABL-transformed cells, CRKL but not CRK II, appears to form complexes which potentially link BCR/ABL, c-ABL, C3G, and SOS to the protooncoprotein, p120CBL.

Adaptor Proteins, Signal Transducing↗