In order to ascertain whether p53 has a role in chronic myeloid leukemia hematopoietic progenitor response to the innovative tyrosine kinase inhibitor STI571 (Imatinib), we overexpressed a wild type (wt) p53 construct in the K562 cell line, generated from a human blast crisis and lacking endogenous p53. Wt p53 overexpression was associated with a significant reduction of bcr-abl expression levels resulting, at least in part, from post-transcriptional events affecting the stability of p210 bcr-abl fusion protein. Moreover, we demonstrated that p53 overexpression enhances the commitment to the apoptotic death fate of K562 following its in vitro exposure to 1 µM STI571. Multiple mechanisms are involved in p53 impact on K562 survival: Most importantly, we found that a greater reduction of bcr-abl transcription by STI571 was associated with the overexpression of wt p53. Further studies are required to elucidate the mechanisms involved in the transcriptional repression of bcr-abl by STI571 and p53 and in their synergic effects on the clonal hematopoiesis of chronic myeloid leukemia.
G.Brusa, M.Mancini, F.Campanini, A.Calabrò, E.Zuffa, E.Barbieri, et al. (2005). Tyrosine kinase inhibotr STI571 (Imatinib) cooperates with wild type p53 on k562 cell line to enhance its pro-apoptotic effets. ACTA HAEMATOLOGICA, 114, 150-154 [10.1159/000087889].
Tyrosine kinase inhibotr STI571 (Imatinib) cooperates with wild type p53 on k562 cell line to enhance its pro-apoptotic effets
BARBIERI, ENZA;SANTUCCI, MARIA ALESSANDRA
2005
Abstract
In order to ascertain whether p53 has a role in chronic myeloid leukemia hematopoietic progenitor response to the innovative tyrosine kinase inhibitor STI571 (Imatinib), we overexpressed a wild type (wt) p53 construct in the K562 cell line, generated from a human blast crisis and lacking endogenous p53. Wt p53 overexpression was associated with a significant reduction of bcr-abl expression levels resulting, at least in part, from post-transcriptional events affecting the stability of p210 bcr-abl fusion protein. Moreover, we demonstrated that p53 overexpression enhances the commitment to the apoptotic death fate of K562 following its in vitro exposure to 1 µM STI571. Multiple mechanisms are involved in p53 impact on K562 survival: Most importantly, we found that a greater reduction of bcr-abl transcription by STI571 was associated with the overexpression of wt p53. Further studies are required to elucidate the mechanisms involved in the transcriptional repression of bcr-abl by STI571 and p53 and in their synergic effects on the clonal hematopoiesis of chronic myeloid leukemia.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.