Aurora-A kinase nuclear expression in chronic lymphocytic leukemia

Inamdar, Kedar; O’Brien, Susan; Sen, Subrata; Keating, Michael J.; Nguyen, Martin; Wang, Xuemei; Fernández, Michael; Thomázy, Vilmos; Medeiros, L. Jeffrey; Bueso‐Ramos, Carlos E.

doi:10.1038/modpathol.2008.173

Cited by 11 publications

(6 citation statements)

References 28 publications

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“…We extended the comparison of the two kinase centric affinity methods to the selectivity profiling of the small molecule Aurora kinase inhibitor tosazertib. Aurora kinases are abnormally expressed in a number of malignancies including leukemia. − As a consequence, a number of small molecule drugs have been developed that target the activity of these kinases. The biotechnology firm Vertex developed tozasertib (VX-680 or MK-0457) as a potent and selective Aurora kinase inhibitor which blocks cell cycle progression and induces apoptosis in a number of tumor types. − Tozasertib inhibits all three Aurora Kinases (A, B, C) at low nanomolar doses in biochemical kinase assays and displays 100-fold selectivity over 55 other kinases tested in the same assay .…”

Section: Resultsmentioning

confidence: 99%

Comparing Immobilized Kinase Inhibitors and Covalent ATP Probes for Proteomic Profiling of Kinase Expression and Drug Selectivity

et al. 2013

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Kinases are involved in the regulation of many cellular processes and aberrant kinase signaling has been implicated in human disease. As a consequence, kinases are attractive drug targets. Assessing kinase function and drug selectivity in a more physiological context is challenging and often hampered by the generally low expression level of kinases and the extensive post-translation modification in vivo. Kinase drug selectivity screens by chemical proteomics have gained attention because they allow the profiling of hundreds of kinases against one drug at the same time. Here, we directly compared two such methods, notably, immobilized broad spectrum kinase inhibitors (kinobeads) and active site labeling using desthiobiotin-ATP and -ADP probes. Affinity purification of ∼ 100 kinases by either kinobeads or ATP/ADP probes was readily achieved using 1 mg of cellular protein. Bioinformatic analysis revealed a high degree of complementarity of the two techniques. Kinobeads covered the Tyrosine Kinase family particularly well and ATP probes enriched higher numbers of STE family kinases. A consecutive combination of both enrichment strategies therefore allowed for the coverage of a larger part of the kinome than any one technique alone. While kinobeads are very selective for kinases, the ATP/ADP probes also enriched a large number of other nucleotide binding proteins. Both methods were applied to the selectivity profiling of the small molecular Aurora kinase inhibitor tozasertib in K562 cells. Our data confirmed Aurora A, B, and BCR-ABL as the main targets of tozasertib and identified TNK1, STK2, RPS6KA1, and RPS6KA3 as submicromolar off targets.

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Section: Resultsmentioning

confidence: 99%

Comparing Immobilized Kinase Inhibitors and Covalent ATP Probes for Proteomic Profiling of Kinase Expression and Drug Selectivity

et al. 2013

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“…Yet, CLL also exhibits a proliferative component. We suspect that this proliferative component is important in disease progression,3, 7, 23 and that activation of EBV may provide proliferative signals.…”

Section: Discussionmentioning

confidence: 99%

Epstein‐Barr virus latent membrane protein 1 mRNA is expressed in a significant proportion of patients with chronic lymphocytic leukemia

Tarrand

Keating

Tsimberidou

et al. 2010

Cancer

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BACKGROUND: Epstein‐Barr virus (EBV) infection has been associated with Richter transformation in patients with chronic lymphocytic leukemia (CLL). METHODS: A direct isothermal mRNA amplification method was developed for detection of EBV latent membrane protein 1 (LMP1) mRNA transcriptional activity in the peripheral blood of 135 chronic lymphocytic leukemia patients and 98 hematologically healthy control subjects. RESULTS: EBV LMP1 mRNA transcripts were found in 19 of 135 (14%) of the CLL cases, but only 1% of the healthy controls (P < .0001). In contrast, 23 solid tumor patients tested negative for EBV LMP1 transcripts. In a later cohort of patients after hematopoietic stem cell transplantation, 4 of 7 patients with Hodgkin lymphoma or Burkitt lymphoma had EBV LMP1 detected. In a preliminary analysis, outcome data were available for 88 of the 135 patients with CLL. EBV LMP1 mRNA positivity was associated with a significantly increased degree of histologically demonstrated bone marrow involvement by CLL (P = .003, Mann‐Whitney U test). CONCLUSIONS: EBV LMP1 mRNA transcriptional activity was observed in a significant proportion of CLL patients. Transcription of the EBV LMP1, a late gene with known transforming potential in vitro, suggests that EBV activation plays a role in CLL disease progression. Thus, EBV LMP1 expression in CLL patients may be a factor involved in the genesis of refractory disease. Cancer 2010. © 2010 American Cancer Society.

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“…4 Thus, it is not unexpected that these kinases have been described to be related with chromosomal instability, agressive growth and poor outcome in leukemia and in various malignancies like breast, bladder, ovarian, pancreatic and colon cancer. 1,[5][6][7][8] This group of kinases consists of three highly related kinases, known as AURKA (alias STK6/STK15/AurA), AURKB (alias STK12/STK5/AurB) and AURKC (alias STK13/AurC) in mammals. AURKA and -B are expressed in the majority of normal cell types.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic profiling of Aurora kinase B is associated with overall survival in metastatic colorectal cancer

Pohl

Azuma²,

Zhang

et al. 2010

Pharmacogenomics J

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Aurora kinases are conserved eukaryotic serine-threonine kinases, which serve as key regulators of mammalian mitosis. Several studies revealed a distinct correlation between inaccurate chromosome segregation, leading to chromosomal number instability, cancer progression and poor outcome. The aim of this study was to investigate the correlation of Aurora kinases A (AURKA) and B (AURKB) with overall survival (OS) by quantifying gene expression analysis and evaluation of single-nucleotide polymorphisms (SNPs) in human colorectal cancer samples and assessing the associations with clinicopathological features. We evaluated intratumoral gene expression levels and SNPs of AURKA and -B from 41 patients with metastatic colorectal cancer (mCRC). Patients with a high expression level of AURKB (41.28) lived significantly shorter (n ¼ 11, median OS ¼ 6.4 months, 95% confidence interval (CI): 3.0-14.5 months) compared with patients with a low expression level (p1.28) (n ¼ 30, median OS ¼ 18.4 months, 95% CI: 14.7-27.8 months, P ¼ 0.026, Wald's test). Patients harboring any G-allele in AURKB 885A4G showed a significantly decreased OS (P ¼ 0.05, log-rank test). We did not find any associations with clinicopathological variables and AURKA gene expression levels. Our results suggest a potential role for AURKB inhibition in patients with mCRC; thereby supporting its potential role as a target in mCRC.

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Aurora-A kinase nuclear expression in chronic lymphocytic leukemia

Cited by 11 publications

References 28 publications

Comparing Immobilized Kinase Inhibitors and Covalent ATP Probes for Proteomic Profiling of Kinase Expression and Drug Selectivity

Comparing Immobilized Kinase Inhibitors and Covalent ATP Probes for Proteomic Profiling of Kinase Expression and Drug Selectivity

Epstein‐Barr virus latent membrane protein 1 mRNA is expressed in a significant proportion of patients with chronic lymphocytic leukemia

Pharmacogenetic profiling of Aurora kinase B is associated with overall survival in metastatic colorectal cancer

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