Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells

Druker, Brian J.; Tamura, Shu; Buchdunger, Elisabeth; Ohno, Sayuri; Segal, Gerald M.; Fanning, Shane; Zimmermann, J.; Lydon, Nicholas B.

doi:10.1038/nm0596-561

Cited by 3,229 publications

(2,113 citation statements)

References 43 publications

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“…K562 cells express Bcr-Abl (Lozzio and Lozzio, 1975) and display constitutively active STAT5. STI-571 (Gleevec, imatinib mesylate) directly inhibits Bcr-Abl, leading to inhibition of STAT5 activation (Druker et al, 1996). Treatment of K562 cells with STI-571 resulted in inhibition of both STAT5a and STAT5b phosphorylation ( Figure 1g).…”

Section: Resultsmentioning

confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high interspecies homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

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Section: Resultsmentioning

confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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“…24 And Imatinib selectively inhibits EGFR to certain extent. 32 Through the inhibition of EGFR, Imatinib may decrease the epithelial proliferation, migration and wound healing or influence the blood-retinal barrier, leading to the occurrence of toxicity. 33,34 Compared with C allele, rs10258429 T allele increased the risk of conjunctival hemorrhage significantly with OR of 7.061.…”

Section: Discussionmentioning

confidence: 99%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

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Imatinib-induced ophthalmological side-effects, including conjunctiva hemorrhage and periorbital oedema, although very common and still remain relatively little understood. The present study investigated the effects of genetic polymorphisms of drug targets and membrane transporters on these side effects. We found that the minor allele of EGFR rs10258429 and SLC22A1 rs683369 were significant risk determinants of conjunctival hemorrhage with OR of 7.061 (95%CI = 1.791-27.837, P = 0.005 for EGFR rs10258429 CT +TT vs CC), and 4.809 (95%CI = 1.267-18.431, P = 0.021 for SLC22A1 rs683369 GG+CG vs CC). The minor allele of SLC22A5 rs274558 and ABCB1 rs2235040 were protective factors to periorbital oedema with OR of 0.313 (95%CI = 0.149-0.656, P = 0.002 for SLC22A5 rs274558 AA+AG vs GG), and 0.253 (95%CI = 0.079-0.805, P = 0.020 for ABCB1 rs2235040 CT vs CC). These results indicated that variants in EGFR, SLC22A1, SLC22A5 and ABCB1 influenced the incidence of Imatinib-induced ophthalmological toxicities, and polymorphism analyses in associated genes might be beneficial to optimize Imatinib treatment.

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“…The concept of targeted therapies (‘magic bullets’) raised high expectations, which were initially fueled by the clinical efficacy of imatinib in chronic myeloid leukemia (CML) patients (Druker et al., 1996, 2006; Weinstein, 2002). Tempering such optimism, however, have been subsequent observations that many mechanism‐targeted drugs have relatively modest clinical benefit, in terms of overall survival, and often in only a fraction of patients with tumors expressing the drug target and hence predicted to benefit (de Bono and Ashworth, 2010; Haber et al., 2011; Martini et al., 2011; Sawyers, 2009).…”

Section: Variable Responses To Targeted Therapies Reveal and Motivatementioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.

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Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells

Cited by 3,229 publications

References 43 publications

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

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