Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-kit proto-oncogen (CD 117) has been shown to be present in several cell types including normal and neoplastic hemopoietic cells. Among normal BM cells, CD117 expression has been found in about half of the CD34+ precursors including progenitors committed to the erythroid, granulo-monocytic, and megakaryocytic cell lineages. In addition, strong CD117 expression is detected in bone marrow mast cells as well as in a small subset of NK cells displaying strong reactivity for CD56, and in a relatively important proportion of CD3 /CD4 /CD8 prothymocytes. These results suggest that CD117 expression can be detected in both myeloid and lymphoid lineages although for the lymphoid lineage it would be restricted to a small NK-cell subset and early T-cell precursors. In acute leukemias CD117 expression was initially associated with AML. Nevertheless, at present it is well established that CD 117 expression may also be found in a relatively important proportion of T-ALL while it is usually absent in B-lineage ALL. Moreover, recent studies have shown that in about one-third of multiple myeloma cases and patients with monoclonal gammopathy of undetermined significance plasma cells display reactivity for CD1117. The prognostic influence of CD117 expression has not yet been clearly established. The analysis of this marker may also be of value for the investigation of minimal residual disease (MRD). It has been suggested that CD117 in combination with other antigens may be of great help for the identification of leukemia-associated phenotypes that could be used to monitor MRD in both acute myeloid leukemias and multiple myeloma patients achieving morphological complete remission.
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PMID:Expression of the c-kit (CD117) molecule in normal and malignant hematopoiesis. 971 8

The association of mast cell diseases and some hematologic malignancies, usually myeloproliferative disorders, myelodysplastic syndromes, and acute leukemia is well recognized. We report the case of a patient with telangiectasia macularis eruptiva perstans, a rare form of cutaneous mastocytosis, and multiple myeloma, an association that has been described only twice in the literature. Parallel improvement of both conditions was observed under chemotherapy regimens for multiple myeloma. Pathogenesis remains unclear, although the abnormalities in the c-kit pathway may play a role in the proliferation of cells from both lineages.
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PMID:Telangiectasia macularis eruptiva perstans and multiple myeloma. 1104 37

Angiogenesis is an important component of the pathogenesis of hematologic malignancies. A negative prognostic implication of increased angiogenesis has been established for acute and chronic myeloid and lymphocytic leukemias, myeloproliferative diseases, multiple myeloma, non-Hodgkin's lymphoma (NHL), and hairy cell leukemia. An association between the return of increased marrow vascularity to normal levels and durability of response has been established in some of these diseases. Elevated levels ofproangiogenic factors have been associated with a poor prognosis in the acute and chronic leukemias, multiple myeloma, and NHL. These data lend support to the reduction of activity of proangiogenic factors as a therapeutic modality. Vascular endothelial growth factor (VEGF) has been implicated as the major proangiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. A direct relationship between VEGF and leukemic blasts and malignant plasma cells has been established, but VEGF may have a function distinct from its role in angiogenesis. Current protocols with anti- VEGF agents in patients with hematologic malignancies involve the use of monoclonal antibody, blockers of the VEGF-receptor tyrosine kinase pathway, thalidomide (Thalomid) and its analogs, and cyclooxygenase inhibitors. The receptor tyrosine kinase inhibitors also affect platelet-derived growthfactor, c-kit, and Flt-3 to varying degrees, considerably broadening their potential efficacy. This review will summarize several angiogenesis inhibitors in clinical development.
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PMID:The emerging role of angiogenesis inhibitors in hematologic malignancies. 1210 77

Multiple myeloma (MM) is the most common plasma cell dyscrasia. Conventional therapy results in a median survival of 3-5 years. Patients with B-cell disorders and coexistent HER-2/neu overexpression in solid tumors have a poorer prognosis than those without an underlying B-cell disorder. This, and the recent success of the tyrosine kinase inhibitor, imatinib mesylate in chronic myelogenous leukemia, led us to evaluate the incidence and role of c-kit (CD117) and HER-2/neu overexpression in MM. We conducted a retrospective study to determine the incidence of HER-2/neu and c-kit overexpression in MM. HER-2/neu overexpression was evaluated using the DAKO Hercep test and c-kit overexpression was assessed using conventional immunohistochemistry (IHC); 69 patients with a diagnosis of MM were identified, of whom, 31 patients (19 males and 12 females) had an adequate pathological specimen available for IHC testing; 4 out of 31 patients (12.9%) showed HER-2/neu overexpression, while 5/31 (16.13%) showed CD117 expression. Two patients (6.45%) showed both HER-2/neu and c-kit overexpression. Although both HER-2/neu and c-kit are not expressed very frequently in patients with MM, there appears to be a subgroup of patients in whom, either one or both these oncogenes is overexpressed. Given our small sample size, it is difficult to comment on the effect of CD117 and/or HER-2/neu overexpression on survival. Future larger studies are needed to define the association in MM and to determine if the presence of one (CD117 or HER-2/neu) has an effect on overexpression of the other oncoprotein. Furthermore, it would be beneficial to identify the molecular nature of the interplay between HER-2/neu and c-kit, if any. Target-directed signal transduction inhibition therapy using tyrosine kinase inhibitors, may be a distinct possibility in a select group of patients with MM.
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PMID:Immunohistochemical identification of HER-2/neu overexpression and CD117 (c-kit) expression in multiple myeloma. 1261 38

c-Kit has been shown to be mutated in several types of tumours, and its activity has been correlated with increased proliferation rates in a subset of multiple myeloma (MM) patients. We have investigated the effect of imatinib mesylate (STI571), an inhibitor of c-Kit, on MM cells. STI571 inhibited the proliferation of MM cells by arresting cell cycle progression. Western blotting of cell cycle proteins showed that STI571 increased the levels of p21 and p16. MM cells expressed abl, but its level of tyrosine phosphorylation was low and unaffected by treatment with STI571. c-Kit was also expressed in certain MM cell lines, and its phosphorylation was stimulated by stem cell factor. However, the failure to detect the receptor protein in other MM cell lines in which cell proliferation was inhibited by STI571 suggests that its effect on these c-Kit-negative MM cell lines might be caused by the action of the drug on yet unknown targets. STI571 inhibited the proliferation of MM cells resistant to dexamethasone or melphalan and had an additive effect when combined with dexamethasone. Efforts to understand the action of STI571 in MM cells may help to identify these potentially useful targets in the treatment of this and other disorders.
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PMID:Imatinib mesylate (STI571) inhibits multiple myeloma cell proliferation and potentiates the effect of common antimyeloma agents. 1463 77

Interstitial cells of Cajal (ICC) are pacemaker cells for the spontaneous muscular contractions and neuromodulators that mediate neurotransmission from enteric neurons to smooth muscle cells in the gastrointestinal (GI) tract. They express c-Kit, and the antibody for c-Kit (especially ACK2) has been a useful tool for functional and morphological studies. ACK2, however, does not work on tissues fixed with paraformaldehyde, and not all ICC express c-Kit in human. Therefore, in order to find a new marker of ICC and/or new antibody resisting aldehyde fixation, we produced a new monoclonal antibody that identifies ICC and then investigated the properties of its antigen. Isolated ICC were used for immunization. Hybridomas fused with myeloma SP2 were screened by immunohistochemistry. ACK2 and each antibody were applied on serial sections, and the clone producing anti-ICC antibody (AIC) that stains ICC was established. The distribution of AIC immunopositive cells was examined in other organs and also GI muscles of W/Wv mice. The biochemical properties were studied using dot blot analysis. AIC recognized ICC; however, distribution of immunopositive cells in W/Wv mice and other organs was different from that of c-Kit. The immunoreactivity was stable for paraformaldehyde but was blocked by either Triton X-100 or SDS. In conclusion, new antibody AIC recognized ICC but the antigen was not c-Kit, which confirms the existence of good markers of ICC besides c-Kit. Although the antigen has not been isolated, AIC is suitable for morphological study and is useful for investigation of ICC in c-Kit mutants.
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PMID:New monoclonal antibody (AIC) identifies interstitial cells of Cajal in the musculature of the mouse gastrointestinal tract. 1529 91

The surface expression of CD117 antigen (c-kit) on plasma cells from 158 multiple myeloma (MM), 12 plasma cell leukemia (PCL), 7 MGUS, 7 IgM lymphoplasmacytic lymphoma patients and 10 healthy subjects has been analyzed by flow cytometry using triple staining with the monoclonal antibodies CD138, CD117 and CD38. The antigen expression intensity was calculated as relative fluorescence intensity (RFI) and for direct quantitative analysis the QuantiBRITE test (Becton Dickinson) was applied. Antibody bounding capacity (ABC) was calculated using QuantiCALC software. CD117 antigen was present in 49/158 MM, 5/12 PCL and 5/7 MGUS patients. The RFI values ranged from 0.2 to 20.2 in particular MM patients (mean: 11.0+/-5.3; median 11.5) while the number of CD117 binding sites (ABC) on MM plasma cells ranged from 637 to 6217 (mean: 3029+/-1568; median 2946) (r=0.8328). In responsive to chemotherapy c-kit positive MM patients the percentage of CD117+ plasma cells in the bone marrow decreased significantly while in c-kit negative MM patients the percentage of CD117+ cells in bone marrow did not change and remained in the normal limits. When comparing the clinical and biological disease characteristics (monoclonal protein isotype, albumin, beta2-microglobulin, lactate dehydrogenase, stage of disease, response to chemotherapy, survival time) of c-kit positive and c-kit negative cases, no significant differences were found. In CD117 positive PCL cases expression of CD117 was detected in bone marrow plasma cells as well as in peripheral blood plasma cells. Normal plasma cells and those in IgM lymphoplasmacytic lymphoma did not show reactivity for the CD117 antigen. We conclude that it may be rationale to consider usefulness of therapy with tyrosine kinase inhibitors in the management of c-kit positive plasma cell proliferations. In one third of MM and PCL patients c-kit antigen could be considered as a "tumor associated marker" and together with CD38 and CD138 it may be of value for the identification of the malignant clone in minimal residual disease as it was first suggested by Spanish authors.
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PMID:C-kit receptor (CD117) expression on plasma cells in monoclonal gammopathies. 1551 18

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.
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PMID:Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines. 1587 Jul 11

Imatinib is a selective protein tyrosine kinase inhibitor currently used in the treatment of chronic myeloid leukaemia (CML). It specifically suppresses the growth of bcr-abl expressing CML progenitor cells by blocking the ATP-binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet derived growth factor receptor (PDGFR), abl-related gene and stem cell factor receptor, c-kit, protein tyrosine kinases. It is through inhibition of c-kit that imatinib is also used clinically in the treatment of gastrointestinal stromal tumours. We have recently demonstrated that imatinib also specifically targets the macrophage colony stimulating factor receptor, c-fms, at therapeutic concentrations. Although this finding has important implications with regard to potential side effects in patients currently receiving imatinib therapy, these results suggest that imatinib may also be useful in the treatment of diseases where c-fms is implicated. This includes breast and ovarian cancer and inflammatory conditions such as rheumatoid arthritis. We also speculate that imatinib may be used in diseases where bone destruction occurs due to excessive osteoclast activity, such as in the haematologic malignancy, multiple myeloma.
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PMID:Inhibition of c-fms by imatinib: expanding the spectrum of treatment. 1591 50

Although imatinib was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases including c-kit. As pre-clinical data, 126 patients with plasma cell disorders and 19 controls were evaluated for c-kit expression. Patients were eligible for the treatment trial if they had relapsed/refractory myeloma. The primary end-point of the study was response. Of the 145 studied before the trial, c-kit expression was present on the bone marrow plasma cells of control (11%), AL amyloid (53%), MGUS (47%), SMM (67%) and MM (42%) patients. Twenty-three MM patients were enrolled on the therapeutic trial (imatinib 400 mg daily) and 52% had positive c-kit staining. There were no responses. The median duration of treatment was 48 days (range: 12-349). Patients ended treatment due to progressive disease (18 patients), death (3) and other (2). The data suggest that imatinib is not an active agent in patients with relapsed or refractory multiple myeloma.
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PMID:A phase II trial of imatinib in patients with refractory/relapsed myeloma. 1632 25


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