Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistant (MDR) phenotype is characterized by a defect in drug accumulation caused by overexpression of a transmembrane glycoprotein, the P-glycoprotein (P-gp). MDR phenotype can be characterized either with monoclonal antibodies raised against P-gp or with functional tests, most often based on the incorporation of fluorescent compounds. In the present study, data obtained with the monoclonal antibodies C219, JSB1 and MRK16 are compared to those of functional tests performed by flow cytometry including uptake of daunorubicin (DNR), Rhodamine 123 (Rh 123) or Hoechst 33342. Sensitive and resistant cell lines K562S, K562R, KBA1 and KB31, derived either from a human chronic myeloid leukemia or from a human epithelial carcinoma, were used. In resistant cells, P-gp expression was revealed with either the monoclonal antibodies C219, JSB1 or MRK-16. The most specific results were obtained with MRK-16. With functional tests, no matter which dyes were used, the fluorescence was always stronger in sensitive than in resistant cells. However, with DNR and Hoechst 33342, an incorporation of these dyes was exhibited in resistant cells. This phenomenon was not observed with Rh 123, which makes it possible to distinguish clearly between sensitive and resistant cells and to detect as few as 1% of resistant cells. Because of its high sensitivity, the functional test involving incorporation of Rh 123 was successfully used in acute myeloid leukemia to detect multichemoresistant cells.
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PMID:Evaluation of multidrug resistant phenotype by flow cytometry with monoclonal antibodies and functional tests. 765 50

Chronic myeloid leukaemia (CML) is a well known model of a disease refractory to chemotherapy, including anthracyclines and other drugs that are believed to be pumped out of the cells by a 170 Kd transmembrane glycoprotein (P170). In 35 cases of Ph+ CML we investigated the reactivity of leukaemic cells to a P170-directed monoclonal antibody (MRK-16), by means of flow cytometry. P170 overexpression was found in 4/14 (29%) chronic phase CML cases and in 16/23 (70%) accelerated and blastic phase CML cases (P = 0.01). The same cells were assayed for their ability to retain Daunorubicin and Idarubicin after 2-hours in vitro incubation with 1000 ng/ml of either drug. It was found that anthracycline cell concentration was negatively related with the degree of the reactivity to MRK-16. In accelerated and blastic phase, CML cells simultaneously expressed P170 and the stem cell related marker, CD34. These data confirm that Ph+ leukaemic cells overexpress P170, show that P170 overexpression is functionally relevant, and suggest that P170-related multidrug resistance may be an important factor for chemotherapy failure in Ph+ CML.
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PMID:P170 glycoprotein expression and impaired anthracycline retention in chronic myeloid leukaemia. 858 Jul 98

DCC (Deleted in Colorectal Cancer) is a putative tumor suppressor gene located on chromosome band 18q21. Allelic deletions of one DCC locus have been found in more than 70% of colorectal carcinomas. Loss of DCC expression has been detected in 80% of all colorectal cancers and in many other types of tumor. DCC is expressed in normal bone marrow and peripheral lymphocytes, nevertheless DCC expression was absent or greatly reduced in 30% of acute leukemias and in 25% of Chronic Myelogenous Leukemias (CML). DCC encodes a transmembrane glycoprotein closely related to the adhesion molecules of the Neural Cell Adhesion Molecule (N-CAM) family. Glycoproteins of this family function like cell surface receptors and are involved in the regulation of many functions including cell recognition and cell differentiation. Highly specialized adhesion molecules participate in the regulation of hemopoiesis by mediating the interactions of hemopoietic cells with the components of the bone marrow microenvironment. Therefore, loss of DCC, as well as loss or alteration of other adhesion receptors, could contribute to leukemogenesis by impairing the interactions of the hemopoietic cells with the bone marrow microenvironment.
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PMID:DCC (deleted in colorectal cancer) inactivation in hematological malignancies. 858 Aug 31

Signal-regulatory proteins (SIRPs) comprise a novel transmembrane glycoprotein family involved in the negative regulation of receptor tyrosine kinase-coupled signaling pathways. To analyze the expression and function of SIRPs, we prepared soluble recombinant fusion proteins of the extracellular regions of SIRPalpha1 and SIRPalpha2, as well as a variety of monoclonal antibodies (MoAbs) against these domains. The antibodies reacted predominantly with monocytes, granulocytes, dendritic cells, and their precursors, as well as with bone marrow CD34(+), AC133(+), CD90(+) hematopoietic stem/progenitor cells. In contrast, SIRP expression was absent or significantly reduced on the majority of myeloid blasts from patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). Functional studies showed that the extracellular domains of SIRPalpha1 and SIRPalpha2 support adhesion of a number of primary hematopoietic cells and cell lines. This interaction could be blocked by 4 of 7 SIRPalpha1-reactive MoAbs. In addition, SIRPalpha1 and SIRPalpha2 competed for the same cell binding site, suggesting a common widely expressed SIRP ligand. In an approach to identify this molecule, MoAbs were generated against the SIRP-binding cell line CCRF-CEM, and MoAb CC2C6 was selected because of its capacity to inhibit cell binding to SIRPalpha1. Further analysis showed that this antibody recognized CD47, a ubiquitously expressed plasma membrane protein previously implicated in integrin function, host defense action, and neutrophil migration. In this study, we identify CD47 as the extracellular ligand for human SIRP and show that these two counterreceptors are involved in cellular adhesion.
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PMID:Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. 1057 74

Acute myeloid leukemia (AML) has a poor prognosis due to treatment-resistant relapses. A humanized anti-CD33 antibody (Mylotarg) showed a limited response rate in relapsed AML. To discover novel AML antibody targets, we selected a panel of single chain Fv fragments using phage display technology combined with flow cytometry on AML tumor samples. One selected single chain Fv fragment broadly reacted with AML samples and with myeloid cell lineages within peripheral blood. Expression cloning identified the antigen recognized as C-type lectin-like molecule-1 (CLL-1), a previously undescribed transmembrane glycoprotein. CLL-1 expression was analyzed with a human anti-CLL-1 antibody that was generated from the single chain Fv fragment. CLL-1 is restricted to the hematopoietic lineage, in particular to myeloid cells present in peripheral blood and bone marrow. CLL-1 is absent on uncommitted CD34(+)/CD38(-) or CD34(+)/CD33(-) stem cells and present on subsets of CD34(+)/CD38(+) or CD34(+)/CD33(+) progenitor cells. CLL-1 is not expressed in any other tissue. In contrast, analysis of primary AMLs demonstrated CLL-1 expression in 92% (68 of 74) of the samples. As an AML marker, CLL-1 was able to complement CD33, because 67% (8 of 12) of the CD33(-) AMLs expressed CLL-1. CLL-1 showed variable expression (10-60%) in CD34(+) cells in chronic myelogenous leukemia and myelodysplastic syndrome but was absent in 12 of 13 cases of acute lymphoblastic leukemia. The AML reactivity combined with the restricted expression on normal cells identifies CLL-1 as a novel potential target for AML treatment.
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PMID:C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. 1554 16

Imatinib mesylate (STI571) is an oral 2-phenylaminopyrimidine derivative that acts as a selective inhibitor against several receptor tyrosine kinases and has been viewed as one of the therapeutic success stories of the 21st century. Imatinib was first shown to inhibit the causative molecular translocation in chronic myelogenous leukemia, BCR-ABL. Because imatinib could also inhibit the activity of KIT, a 145-kD transmembrane glycoprotein, and because gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the digestive tract, are characterized by expression of a gain-of-function mutation in KIT, imatinib was used in therapeutic trials of GISTs beginning in 1999. The initial success has now resulted in more widespread use of imatinib for the treatment of patients with GIST. Molecular genetic studies have shown that most GISTs possess a KIT mutation in exon 9, 11, 13, or 17. Clinically, GIST patients with KIT exon 11 mutations (ie, the juxtamembrane region) are the most prevalent and sensitive to imatinib. In addition to the inhibitory effect on KIT, imatinib also inhibits the activity of mutant platelet-derived growth factor receptor-alpha (PDGFRalpha) found in a subset of GIST. What is becoming evident is that there are patients with GIST who lack mutations in KIT or PDGFRalpha, or possess "imatinib-resistant" mutations (such as exon 17 mutations in KIT and exon 18 mutations in PDGFRalpha). These patients typically do not respond well to imatinib therapy. Therefore, identifying additional genetic factors that contribute to the pathogenesis of GIST, independent of KIT and PDGFRalpha, will be important in developing additional anti-GIST therapies. As one might suspect from previous experiences with antitumor therapies, primary and secondary resistance to imatinib is also becoming a major clinical problem in the treatment of this disease. Therefore, new drugs that can serve as alternative therapies in imatinib-resistant patients with GIST or that can be used in combination with imatinib will be needed. As with most recent efforts to derive novel molecular target therapies to treat cancer, improved therapy of GIST will continue to benefit from advances in the molecular characterization of this disease.
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PMID:Molecular research directions in the management of gastrointestinal stromal tumors. 1624 52