Published online 16 June 2009
Haematologica, Vol 94, Issue 7, 944-955 doi:10.3324/haematol.2008.004861
Copyright © 2009 by Ferrata Storti Foundation
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Malignant Lymphomas

The effect of the cyclin-dependent kinase inhibitor flavopiridol on anaplastic large cell lymphoma cells and relationship with NPM-ALK kinase expression and activity

Paolo Bonvini, Elisa Zorzi, Lara Mussolin, Giovanni Monaco, Martina Pigazzi, Giuseppe Basso, Angelo Rosolen

Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, Italy

Correspondence: Paolo Bonvini, Ph.D., Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, via Giustiniani 3, 35128 Padova, Italy. E-mail:paolo.bonvini{at}unipd.it

Background: The loss of cell cycle regulation due to abnormal function of cyclin-dependent kinases (cdk) occurs in tumors and leads to genetic instability of chemotherapy-resistant cells. In this study, we investigated the effect of the cdk inhibitor flavopiridol in anaplastic large cell lymphomas, in which unrestrained proliferation depends on NPM-ALK tyrosine kinase activity.

Design and Methods: Effects of flavopiridol were examined in ALK-positive and -negative anaplastic large cell lymphoma cells by means of immunoblotting and immunofluorescence analyses to assess cdk expression and activity, quantitative real time reverse transcriptase polymerase chain reaction to measure drug-induced changes in transcription, and FACS analyses to monitor changes in proliferation and survival.

Results: Treatment with flavopiridol resulted in growth inhibition of anaplastic large cell lymphoma cells, along with accumulation of subG1 cells and disappearance of S phase without cell cycle arrest. Consistent with flavopiridol activity, phosphorylation at cdk2, cdk4, cdk9 sites on RB and RNA polymerase II was inhibited. This correlated with induction of cell death through rapid mitochondrial damage, inhibition of DNA synthesis, and down-regulation of anti-apoptotic proteins and transcripts. Notably, flavopiridol was less active in ALK-positive cells, as apoptosis was observed at higher concentrations and later time points, and resistance to treatment was observed in cells maintaining NPM-ALK signaling. NPM-ALK inhibition affected proliferation but not survival of anaplastic large cell lym-phoma cells, whereas it resulted in a dramatic increase in apoptosis when combined with flavopiridol.

Conclusions: This work provides the first demonstration that targeting cdk is effective against anaplastic large cell lymphoma cells, and proves the critical role of NPM-ALK in the regulation of responsiveness of tumor cells with cdk dysregulation.

Key words: anaplastic large cell lymphoma, NPM-ALK, cell cycle.


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Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy
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B. Falini and M. P. Martelli
Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy
Haematologica, July 1, 2009; 94(7): 897 - 900.
[Full Text] [PDF]