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At least 667 records · Page 37Linked to original sources
PubMed2000

Generation of monospecific peptide antibodies to the DNA binding domain of p53.

The DNA binding domain (DBD) is the most mutated region of p53 in tumors and has proven to be relatively resistant to the generation of specific antibodies. Template assembled synthetic peptide (TASP) synthesis of a peptide derived from the DBD creates a highly immunogenic molecule without the need for large carriers such as keyhole limpet hemocyanin (KLH). In addition, a rapid means of generating monoclonal antibodies can be achieved through immunization in conjunction with ABL/MYC retrovirus injection into recipient mice. In this paper, we demonstrate that an antibody generated by this means, KH2, reacts specifically with the DBD of p53. To date, this is the first example of a peptide immunogen used successfully in ABL/MYC monoclonal antibody production. KH2 is also the first example of a monospecific antibody that directly binds to and, by definition, assumes the conformation of the DNA binding region of p53.

Amino Acid Sequence↗
PubMed2004

Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment.

Following the paradigm set by STI571, protein tyrosine kinase inhibitors are emerging as a promising class of drugs, capable of modulating intracellular signaling and demonstrating therapeutic potential for the treatment of proliferative diseases. Although the majority of chronic phase CML patients treated with STI571 respond, some patients, especially those with more advanced disease, relapse. This article reviews the reasons for relapse and, in particular, analyses resistance resulting from Bcr-Abl tyrosine kinase domain mutations at the molecular level. Arguments are based upon the structure of the STI571-Abl complex, which is compared to the crystal structures of PD173955-Abl and PD180970-Abl, which bind to the kinase differently. Strategies to potentially circumvent or overcome resistance are discussed.

Animals↗
PubMed2006

Mechanisms of resistance to imatinib in CML patients: a paradigm for the advantages and pitfalls of molecularly targeted therapy.

One of the challenges of cancer therapeutics is to discover targets unique to the tumor cell population. Constitutively activated tyrosine kinases play a role in the malignant phenotype in a number of different cancers. While the kinases may be present in the normal cell, the cancer cell is often dependent upon the activation of the kinase for the maintenance of malignant growth. Inhibition of kinase activation may therefore selectively inhibit malignant proliferation. In the case of chronic myelogenous leukemia (CML), the activated tyrosine kinase (BCR-ABL) is due to a chromosomal translocation that defines this disease, and is necessary for malignant transformation. Imatinib mesylate (Gleevec, Novartis) is a small molecule tyrosine kinase inhibitor, developed through the chemical modification to be selected for a small number of tyrosine kinases present in human cells. This agent is also orally bioavailable and has been found to be effective in clinical trials. We have learned much through the clinical use of this agent. 1) Specific targeting of activated signal transduction pathways may be effective in inhibiting cancer cells. 2) Cancer cells may not only be inherently resistant to small molecule inhibitors, but may also develop resistance after exposure to the inhibitor. 3) Increased knowledge regarding critical signal transduction pathways, the structure of the molecules that are being targeted and the inhibitors themselves, will allow us to understand resistance as it develops and create new molecules to bypass resistance. We will discuss imatinib as an important example of the success and pitfalls of targeted therapeutics for cancer.

Benzamides↗
PubMed2003

Contribution of abnormal insulin secretion and insulin resistance to the pathogenesis of type 2 diabetes in myotonic dystrophy.

OBJECTIVE: Myotonic dystrophy (MyD), the most common adult form of muscular dystrophy, is often complicated by diabetes. MyD is dominantly inherited and is due to heterozygosity for a trinucleotide repeat expansion mutation in a protein kinase gene able to induce derangement of RNA metabolism responsible of an aberrant insulin receptor expression. RESEARCH DESIGN AND METHODS: To assess insulin sensitivity and secretion before the onset of diabetes, we studied 10 MyD patients, 10 offspring of type 2 diabetes (OFF), and 10 healthy subjects with no family history of diabetes (control subjects) with dual X-ray energy absorption, euglycemic-hyperinsulinemic clamp (40 mU/[m(2). min]) combined with infusion of [6,6-D(2)]-glucose and oral glucose tolerance test (OGTT). RESULTS: MyD had reduced lean body mass, but peripheral insulin sensitivity was not different to that of control subjects in contrast to OFF, which showed insulin resistance. Insulin secretion, obtained by deconvolution of OGTT data, was also shown to be comparable with that of OFF and control subjects (index of beta-cell function = Phi; P = 0.91) even if increased parameters of insulin secretion were found during the first 30 min (Phi(30); P = 0.05) of the oral glucose challenge. Fasting plasma proinsulin concentrations (P = 0.01) and the ratio to insulin (P = 0.01) were increased in MyD patients. The proinsulin levels also failed to be suppressed during the clamp and showed exaggerated response after the OGTT. Increased proinsulin levels were shown to be peculiar of MyD patients when compared with OFF. CONCLUSIONS: In nondiabetic, young MyD patients, insulin sensitivity was preserved, and an increased early secretory response to oral glucose was detected. Abnormal plasma proinsulin levels in the fasting state, during the clamp, and during the OGTT were shown to be secretory dysfunctions peculiar of MyD patients and may be more important than insulin resistance in determining the high risk to develop diabetes in these patients.

Adult↗
PubMed1992

Extremely poor prognosis of pediatric acute lymphoblastic leukemia with translocation (9;22): updated experience.

Approximately five percent of pediatric acute lymphoblastic leukemias (ALL) contain a translocation (9;22)(q34;q11) which results in rearrangement of the bcr and abl genes. At a median follow-up of 5 years, we assessed the prognostic implications of translocation (9;22) in 434 children receiving intensive treatment for ALL. Four-year event-free and overall survivals were only 0% and 20%, respectively, in 15 children with translocation (9;22), but were 81% and 89%, respectively, in 419 children lacking translocation (9;22) (P < 0.001). Based on these findings, we recommend very intensive treatment approaches for all children with translocation (9;22)-positive ALL.

Adolescent↗
PubMed1993

Chronic myeloid leukaemia--the XXI century.

CML has served as a model for study of pathogenesis, evolution and treatment of malignancy for nearly 150 years and will continue to do so. The increasing interest worldwide in biology and medicine and the explosion of activity in molecular biology make it probable that many forms of leukaemia, lymphoma and solid tumours that are lethal today will be readily prevented or cured within the next 20 or 30 years.

Bone Marrow Transplantation↗
PubMed1993

Minimal residual disease after bone marrow transplant for chronic myeloid leukaemia detected by the polymerase chain reaction.

We describe the methodology and application of the polymerase chain reaction to detect BCR-ABL mRNA as a marker for CML cells. The technique is highly sensitive enabling the routine detection of 1 leukaemic cell in 10(5) or 10(6) normal cells and is therefore the most sensitive method available for detecting minimal residual disease. Analysis of marrow or blood from 80 patients after bone marrow transplantation for CML shows that residual leukemia is often detectable for several months but that most subsequently become PCR negative. Patients who relapsed were all PCR positive before the detection of Philadelphia positive metaphases in bone marrow aspirates.

Base Sequence↗
PubMed1993

Will molecular biology contribute to refine prognosis and to select treatment? The Molecular Biology Committee. Italian Cooperative Study Group on Chronic Myeloid Leukemia.

The possible prognostic value of the position of the breakpoint within the M-BCR in patients with Ph1+ CML is still being debated. We analyzed the DNA rearrangements and the transcript types of 244 patients and tried to correlate the data obtained with prognostic features, defined according to Sokal's risk index, and with chronic phase and/or survival duration. The exact location of the breakpoint, either 5' or 3' to the Hind III restriction site within the M-BCR was identified. Moreover, the exact M-BCR subregion was also identified. As a whole, 150 pts were rearranged in the 5' part and 94 in the 3' part of the M-BCR. No correlation was observed between the site of rearrangement on the one hand and the Sokal's prognostic index and survival, on the other. Transcript analysis was performed in 130 patients; 59 carried an a2b2 and 69 an a2b3 pattern. Two patients carried both transcripts. Of the patients rearranged in the 5' area, according to Southern blotting, 29.2% showed an a2b3 transcript. Therefore, RT-PCR analysis allowed a better definition of the breakpoint. However, also the type of transcript did not show any correlation either with risk categories or survival. No difference in response to therapy, either chemotherapy or alpha interferon, was observed between 5' and 3' rearranged patients.

Antineoplastic Agents↗
PubMed1993

Molecular consequences of the BCR-ABL translocation in chronic myelogenous leukemia.

The BCR-ABL translocation of chronic myelogenous leukemia represents a paradigm for the study of translocations that create fusion proteins. The work of many laboratories has clearly established that the BCR-ABL protein can transform cells and cause leukemias in mice. This oncogenic signal appears to involve transduction of a tyrosine kinase signal from the cytoplasm to the nucleus via intermediary proteins such as ras and myc. Although the biological effects of the BCR-ABL fusion protein are well characterized, the normal biological functions of ABL and BCR are only beginning to come to light. ABL is a nuclear tyrosine kinase which binds DNA, suggesting a possible normal role in transcription. BCR has homology to proteins which regulate membrane ruffling. Understanding the normal roles of ABL and BCR will help define the abnormal leukemogenic effects of the BCR-ABL fusion.

Animals↗
PubMed1995

Does the type of BCR/ABL junction predict the survival of patients with Ph1-positive chronic myeloid leukemia?

The prognostic value of the site of DNA rearrangement within the M-BCR on chromosome 22 or of the type of transcript has been debated in the last years. The majority of the studies do not support the hypothesis of a predictive value of such molecular parameters. Results coming from a multicentric, prospective trial, based on alpha-IFN therapy, seem to indicate a better karyotypic response in 3' rearranged patients. The possibility of evoking a cytotoxic immune response directed towards peptides originating from each of the different BCR/ABL junctions constitute an important challenge for the future.

Fusion Proteins, bcr-abl↗
PubMed2002

The BCR/ABL transgene causes abnormal NK cell differentiation and can be found in circulating NK cells of advanced phase chronic myelogenous leukemia patients.

NK cells from the blood of chronic myelogenous leukemia (CML) patients are progressively decreased in number as the disease progresses from chronic phase to blast crisis. We hypothesize that BCR/ABL may be directly responsible by interfering with NK cell differentiation. CD34(+)HLA-DR(+) cells from CML patients were studied for their capacity to differentiate into NK cells. The NK cell cloning frequency was significantly decreased from CML CD34(+)HLA-DR(+) cells compared with cells from normal donors, yet CD34(+)HLA-DR(+) cells gave rise to BCR/ABL(+) NK cells in some patients. This finding prompted us to further investigate circulating NK cells from the blood of CML patients. CD56(+)CD3(-) NK cells were sorted from CML patients and examined by fluorescence in situ hybridization (FISH). In contrast to chronic phase CML, significant numbers of NK cells from advanced phase CML patients were BCR/ABL(+), whereas T cells were always BCR/ABL(-) regardless of the disease stage. To test the effects of BCR/ABL as the sole genetic abnormality, BCR/ABL was transduced into umbilical cord blood CD34(+) cells, and NK development was studied. p210-enhanced green fluorescence protein-transduced cells gave rise to significantly decreased numbers of NK cells compared with enhanced green fluorescence protein transduction alone. In addition, the extrinsic addition of BCR/ABL-transduced autologous CD34(+) cells suppressed the NK cell differentiation of normal umbilical cord blood CD34(+)CD38(-) cells. This study provides the first evidence that BCR/ABL is responsible for the altered differentiation of NK cells and that the NK cell lineage can be involved with the malignant clone in advanced stage CML.

Animals↗
PubMed2003

Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL.

Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.

Blast Crisis↗
PubMedDate not supplied

Detection of chromosomal abnormalities using fluorescence in situ hybridization (FISH).

BACKGROUND: A number of studies have demonstrated the use of molecular cytogenetic techniques for clinical diagnosis. We compared the results of FISH analysis and conventional cytogenetics on different tissue samples for detection of chromosomal aberrations and to assess the utility of FISH assay for clinical diagnosis. METHODS: Karyotypic analysis was carried out on 50 samples--20 peripheral blood samples, 20 bone marrow samples and 10 prenatal (chorionic villi/amniotic fluid) samples. The same chromosome preparations were further subjected to FISH analysis using probes specific for chromosome X, Y, 21 or bcr-abl gene. RESULTS: The results of FISH analysis were in conformity with the cytogenetic results in all the samples except one. FISH analysis could reveal hybridization signals even on poorly spread metaphase chromosomes and interphase nuclei. It was also possible to detect subtle chromosomal aberrations which were not detected using conventional chromosomal analysis. CONCLUSION: FISH is a powerful, sensitive molecular cytogenetic technique which can be used as an adjunct to conventional chromosomal analysis for prenatal diagnosis and the diagnosis and management of cancer patients. FISH analysis should be used as a supplement to conventional cytogenetics.

Amniocentesis↗
PubMed2002

Critical role for cyclin D2 in BCR/ABL-induced proliferation of hematopoietic cells.

Chronic myeloid leukemia is caused by the tyrosine kinase oncoprotein BCR/ABL. Using oligonucleotide arrays to assay mRNAs at different phases of the cell cycle in BCR/ABL-transformed cells, we found that cyclin D2 mRNA was constitutively expressed at high levels throughout the cell cycle, a pattern confirmed by immunoblotting of protein lysates. Bone marrow cells from cyclin D2-deficient strains of mice failed to proliferate in response to infection with a retrovirus carrying BCR/ABL and failed to generate transformed lymphoid cell lines in vitro. These results establish that BCR/ABL promotes cell cycle progression by altering expression of cyclin D2 and that cyclin D2 induction plays a critical role in proliferation of hematopoietic cells by BCR/ABL.

Animals↗
PubMed2002

Fusion between homologous cells, modified epigenetic environment and possible cell cancerization.

For a long time now we have been putting forwards the hypothesis that, when two cells belonging to different tissues of the same organism fuse, the nucleous/nuclei of the resulting "fused" cell could lay into a cytoplasm possibly containing factors influencing the activation or deactivation of genes able to interfere with the differentiation "iter" proper of the parent cells. As a consequence, the fused cells could undergo neoplastic transformation. In order to give an experimental support to such an hypothesis, mononuclear cells and granulocytes were isolated from the white blood cells of the same individual, mixed (at 1/1 ratio) and fused, using polyethylen glycol (PEG). The fused cells were then cultured into a suitable medium, supplemented with phytohemoagglutinin (PHE), a lectin which is able to stimulate at least one of the nuclei. Samples from these cultures were withdrawn at progressive time-intervals and stained with May Grümwald-Giemsa. Microscopic examination showed the appearance of cells morphologically resembling Hodgkin's and Reed Sternberg cells, or leukemic cells. A crown of mononucleated cells was often surrounding such anomalous cells, as happens in the early stage of killer cells action against target cells. In two out of fifty cultures, cells grew without need for serum supply, suggesting the onset of an autocrine system.

Cell Culture Techniques↗