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)

Loss of the inhibition of apoptosis is important in leukemogenesis and may influence the prognosis. Survivin is an inhibitor of apoptosis that shows selective expression during fetal development and in human malignancies. Survivin expression was examined in human leukemias using the reverse transcriptase-polymerase chain reaction. Survivin gene expression was detected in 17 of 31 patients with acute myelocytic leukemia and 11 of 16 patients with acute lymphocytic leukemia but was not identified in normal bone marrow cells. Survivin expression was lower in patients with M3 acute myelocytic leukemia than in patients with other types of acute leukemia. Survivin was not detected in the chronic phase of chronic myelocytic leukemia but was observed in 5 of 7 patients with chronic myelocytic leukemia in blastic crisis. These findings suggest a relationship between survivin gene expression and hematopoietic cell differentiation. In fact, survivin gene expression was down-regulated during the differentiation of HL-60 cells after treatment with dimethyl sulfoxide or all-trans-retinoic acid. Moreover, the disease-free survival rates of patients with survivin expression were lower than in patients without survivin expression. Accordingly, survivin may have a role in leukemogenesis as well as in other malignancies. Detecting survivin may also provide prognostic information.
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PMID:Expression of the antiapoptosis gene survivin in human leukemia. 1193 62

The advanced understanding of the molecular biology and immunology of chronic myeloid leukemia (CML) has led to novel therapeutic strategies unique to this disease. CML responds to immune-mediated therapies, including stem cell transplantation, donor lymphocyte infusion (DLI), and interferon alfa. T cells and other immune effectors are implicated in the mechanisms of action of these immune therapies. Recently, clinical observations supported by laboratory data have demonstrated the presence of CML-specific T cells in patients. Several proteins may potentially act as leukemia-specific antigens for major histocompatibility complex (MHC)-restricted cytotoxicity in CML, and active specific therapies (vaccines) are in development. Antigens under investigation include bcr-abl, PR1, Wilms tumor protein (WT1), minor histocompatibility antigens (mH), CML-66, CML-28, and survivin. Other strategies target vascular endothelial growth factor (VEGF) and heat shock protein 90 (Hsp90) inhibitors or make use of CML-derived dendritic cells (DC).
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PMID:Novel targeted and immunotherapeutic strategies in chronic myeloid leukemia. 1256 15

Survivin, a unique member of the inhibitor of the apoptosis protein (IAPs) family, is over-expressed in many cancers but not in normal differentiated adult tissues. Using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we investigated patterns of survivin gene expression in a group of 12 patients with chronic myeloid leukemia (CML) representing both chronic and blastic phases of the disease. All 6 patients in chronic phase CML were uniformly negative for the survivin transcript, in contrast to 4 Philadelphia chromosome-positive (Ph+) CML patients in blastic crisis, all of whom (100%) were positive for survivin with tangible levels of expression. However, survivin expression was markedly down-regulated in 2 atypical CML patients with Philadelphia chromosome-negative (Ph-) blastic crisis. Our data indicates that up-regulation of survivin expression may be involved in typical CML evolution from the chronic into the blastic phase of the disease.
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PMID:Expression of the antiapoptotic gene survivin in chronic myeloid leukemia. 1268 Jan 51

Survivin has been identified as one of the top 4 transcripts among 3.5 million human transcriptomes uniformly up-regulated in cancer tissues but not in normal tissues. Therefore, we quantitatively determined the messenger RNA (mRNA) expression profile for survivin by a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) technique in 113 patients with leukemias, such as adult T-cell leukemia (ATL), acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia in crisis, and chronic lymphocytic leukemia (CLL), and in 25 cell lines, including 7 ATL cell lines and 15 solid-tumor cell lines. Furthermore, we examined whether the plasma level of survivin protein as measured by enzyme-linked immunosorbent assay (ELISA) substituted for mRNA expression by PCR quantification. Gene expression was quantitatively confirmed to be up-regulated in approximately 90% of ATL and acute leukemia cases and in all of the cell lines tested, whereas it was down-regulated in almost all cases of CLL. Furthermore, with respect to the interpretation of the gene expression findings, attention was paid to standardization with a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in the real-time PCR quantification, because the variability in GAPDH expression among the different cell types was significant. GAPDH expression was relatively low in ATL cells and high in ALL and AML cells. The rates of increase in the levels of survivin protein in the plasma of ATL patients and in the supernatants from in vitro cultures of solid-tumor cell lines were low compared with rates of increase of the mRNA and protein level in the cells, suggesting that the protein levels in plasma do not always reflect survivin expression in tumor cells. Our findings indicate the potential clinical relevance of survivin quantified by real-time PCR but not for the protein level in plasma as determined by ELISA, especially in cases of ATL and acute leukemias.
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PMID:Clinical relevance of survivin as a biomarker in neoplasms, especially in adult T-cell leukemias and acute leukemias. 1529 68

The present study was undertaken to investigate the mechanisms of peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligand-induced apoptosis on human myeloid leukemia K562 and HL-60 cell lines. The results revealed that both 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and troglitazone (TGZ) have significant anti-proliferation- and apoptosis-inducing effects on these two kinds of leukemia cells. Marked morphological changes of cell apoptosis including condensation of chromatin and nuclear fragmentation were observed clearly using Wright's and Hoechst 33258 staining. Reverse transcription-PCR and western blot analyses demonstrated that both survivin and bcl-2 expression were downregulated markedly, while bax expression was upregulated concurrently when apoptosis occurred. We therefore conclude that 15d-PGJ2 and TGZ have significant apoptosis effects on K562 and HL-60 cells in vitro, and that upregulation of bax as well as downregulation of survivin and bcl-2 expression may be the important apoptosis-inducing mechanisms. The results suggest that PPAR-gamma ligands may serve as potential therapeutic agents for both acute and chronic myeloid leukemia.
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PMID:Expression of survivin and bax/bcl-2 in peroxisome proliferator activated receptor-gamma ligands induces apoptosis on human myeloid leukemia cells in vitro. 1564 6

As more and more effective targeted therapeutics have been developed to treat adults with cancer, it is of critical importance to devise appropriate in vitro experimental models to study their use in pediatric patients. Acute lymphoblastic leukemia (ALL) with Bcr-Abl translocation is one of the most difficult to treat and deadly diseases in children. The targeted kinase inhibitor imatinib mesylate has been shown to induce an initial response but resistance often develops. Recently, the geldanamycin family of antibiotics has been found to induce apoptosis in many malignant cells, including adult CML and AML. We describe experiments in which 17-allylamino-17-demethoxygeldanamycin (17-AAG) was evaluated in the context of Bcr-Abl and resistance to imatinib mesylate. Pediatric ALL cell lines with varying Bcr-Abl status and imatinib mesylate sensitivity were generated and their growth inhibition by 17-AAG was studied in vitro. Western blots were used to follow the changes in proteins that correlate with cell survival. Results show that apoptosis was induced in all lines with an increased 50% inhibitory concentration (IC50) for Bcr-Abl positive but imatinib mesylate-resistant cells. Addition of 17-AAG greatly increased imatinib sensitivity in vitro. A decrease in p53, survivin, Her2/neu, and WT1 was seen in cells that expressed these proteins. With some notable exceptions, when combined with 17-AAG, the IC50 of most of the common chemotherapeutic agents decreased. We describe an experimental approach to investigate the complex interaction between Bcr-Abl status, imatinib mesylate sensitivity, and 17-AAG in pediatric ALL. Information from such an approach will provide means to devise combined treatment approaches and to follow their effectiveness in vitro.
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PMID:Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity. 1565 98

In this study, we investigated the expression of survivin (SVV) in 44 patients with typical Ph-positive chronic myeloid leukemia (CML) in different phases of the disease as well as in 20 matched healthy donors. We found a very high SVV expression in a predominant percentage of CML patients. We also observed a significantly increased SVV expression in patients in accelerated/blastic phase of the disease compared to patients in chronic phase. Moreover, SVV expression levels correlated in all CML patients with % of Ph-chromosome positive cells, with Bcr-Abl expression levels and with WBC-count. Based on this finding we suggest that SVV detection and monitoring in CML could represent both a useful biomarker and attractive candidate for devising new targeted and combined therapies in CML.
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PMID:Survivin expression in chronic myeloid leukemia. 1592 62

An increase in the proliferation and resistance to apoptosis of leukemic cells has been found in chronic myeloid leukemia (CML) as the disease evolves from the chronic phase to blast crisis (BC). To contribute to a better knowledge of the molecular mechanisms involved in such biological abnormality, the expression of the survivin gene was studied by quantitative real-time polymerase chain reaction (PCR) in the chronic phase of CML and at BC in 16 patients in whom sequential RNA samples from the 2 phases of the disease were available. Survivin was significantly overexpressed in both the chronic phase and BC as compared with granulocytes from controls. In BC, survivin expression was 7-fold higher than in the chronic phase, with such an increase being more pronounced in the myeloid (17-fold) than in the lymphoid cases (3-fold) (P = 0.03). Cell proliferation was significantly increased at BC, with Ki-67 expression being 2.8-fold higher than in the chronic phase. Despite the overexpression of both survivin and Ki-67 at BC, no significant correlation between their expression levels was observed. These data support a possible role for survivin overexpression in the pathogenesis of the progression of CML. However, further studies are required to elucidate the possible prognostic importance of such biological findings in this disease.
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PMID:Survivin expression in the progression of chronic myeloid leukemia: a sequential study in 16 patients. 1601 9

The Bcr-abl oncogene induces hematopoietic cell transformation and protects cells from apoptosis; however, the mechanisms whereby Bcr-abl blocks apoptosis are poorly defined. We examined whether the inhibitor of apoptosis protein (IAP) family, in particular survivin, are regulated by Bcr-abl. Overexpression of Bcr-abl in Mo7e or BaF3 hematopoietic cells elevated survivin mRNA and protein concomitant with a 4-fold increase in survivin promoter activity. The region of the survivin promoter responding to Bcr-abl was narrowed down to a 116 bp fragment between nucleotides -1,194 and -1,078. The IAP family member IAP-like protein-2 was also up-regulated by Bcr-abl. Disruption of Bcr-abl in Bcr-abl-transduced BaF3 cells by small interfering RNA resulted in 3- to 4-fold reduction in survivin protein confirming the link between Bcr-abl and survivin. Survivin disruption in Bcr-abl-transduced Mo7e cells, or in K562 cells that endogenously express Bcr-abl, by transfection with dominant-negative or antisense survivin constructs promoted apoptosis induced by the Bcr-abl tyrosine kinase inhibitor STI571, which was accompanied by caspase-dependent cleavage of Bcr-abl, mitochondrial membrane potential disruption, and enhanced mitochondrial cytochrome c release. Although ectopic survivin protected K562 cells from apoptosis induced by STI571, it did not protect cells from apoptosis induced either by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of TRAIL plus Hemin. Our results identify a new signal pathway downstream of Bcr-abl, in addition to the Bcl-2 family involved in the antiapoptotic effects of Bcr-abl, and suggest that anti-survivin therapy may have utility in patients with chronic myelogenous leukemia.
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PMID:Disruption of the inhibitor of apoptosis protein survivin sensitizes Bcr-abl-positive cells to STI571-induced apoptosis. 1616 98

KBM5 cells, derived from a patient with blast crisis Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), and imatinib-resistant KBM5 (KBM5-STI571) cells were found to express high levels of survivin. Inhibition of Bcr-Abl by imatinib significantly decreased survivin expression and cell viability in KBM5, but much less so in KBM5-STI571 cells. Inhibition of MEK, downstream of the Bcr-Abl signaling cascade decreased survivin expression and cell viability in both KBM5 and KBM5-STI571 cells. In addition, down-regulation of survivin by a survivin antisense oligonucleotide (Sur-AS-ODN) inhibited cell growth and induced maximal G2M block at 48 hours, whereas cell death was observed only at 72 hours in both KBM5 and KBM5-STI571 cells as shown by annexin V staining. Further, the combination of Sur-AS-ODN and imatinib induced more cell death in KBM5 cells than did either treatment alone. Down-regulating survivin also decreased colony-forming units (CFUs) in blast crisis CML patient samples. Our data therefore suggest that survivin is regulated by the Bcr-Abl/MAPK cascade in Ph+ CML. The facts that down-regulating survivin expression induced cell-growth arrest and subsequent cell death regardless of the cell response to imatinib and enhanced the sensitivity to imatinib suggest the potential therapeutic utility of this strategy in patients with CML, both imatinib sensitive and resistant.
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PMID:Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells. 1625 45


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