Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

<p>Abstract</p> <p>Background</p> <p>The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells.</p> <p>Methods</p> <p>Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels.</p> <p>Results</p> <p>Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited <it>hTERT </it>at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in <it>hTERT </it>gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of <it>hTERT </it>mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec.</p> <p>Conclusions</p> <p>Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the <it>hTERT </it>gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.</p

A retrospective study evaluating the efficacy and safety of bendamustine in the treatment of mantle cell lymphoma

Bendamustine is approved in the United States for relapsed indolent lymphoma. However, it has not been widely studied in mantle cell lymphoma (MCL). We retrospectively reviewed the records of all patients with MCL who were treated with bendamustine at three centers. The primary endpoint was overall response rate (ORR). Thirty patients with MCL received bendamustine, 25 for relapsed disease. After a median follow-up of 12 months, there were 15 complete responses (CRs) with an ORR of 83% (95% confidence interval [CI] 70–97%). Factors significantly associated with longer survival were achieving a CR and classical (versus blastic) variant of MCL. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 23%, 3% and 20%, respectively. There was one case of progressive multifocal leukoencephalopathy 10 months after therapy completion. Bendamustine in combination with rituximab demonstrated a high response rate in this study of patients with predominantly relapsed MCL

Do people from the Jewish community prefer ancestry-based or pan-ethnic expanded carrier screening?

Ancestry-based carrier screening in the Ashkenazi Jewish population entails screening for specific autosomal recessive founder mutations, which are rarer among the general population. As it is now technically feasible to screen for many more diseases, the question arises whether this population prefers a limited ancestry-based offer or a pan-ethnic expanded carrier screening panel that goes beyond the diseases that are frequent in their own population, and is offered regardless of ancestry. An online questionnaire was completed by 145 individuals from the Dutch Jewish community (≥18 years) between April and July 2014. In total, 64.8% were aware of the existence of ancestry-based carrier screening, and respondents were generally positive about screening. About half (53.8%) preferred pan-ethnic expanded carrier screening, whereas 42.8% preferred ancestry-based screening. Reasons for preferring pan-ethnic screening included ‘everyone has a right to be tested', ‘fear of stigmatization when offering ancestry-based panels', and ‘difficulties with identifying risk owing to mixed backgrounds'. ‘Preventing high healthcare costs' was the most important reason against pan-ethnic carrier screening among those in favor of an ancestry-based panel. In conclusion, these findings show that people from the Dutch Jewish community have a positive attitude regarding carrier screening in their community for a wide range of diseases. As costs of expanded carrier screening panels are most likely to drop in the near future, it is expected that these panels will receive more support in the future