Abstract
Core-binding factor (CBF) leukemias are characterized by a high degree of sensitivity to high-dose cytarabine (ARA-C) treatment and by a relatively favorable prognosis compared with most other forms of adult acute myeloid leukemia (AML). The molecular basis of the response to chemotherapy is still being analyzed. The proteinase 3 (PR3) gene codes for a serine protease with a broad spectrum of proteolytic activity. PR3 is involved in the control of proliferation of myeloid leukemia cells, and when it is abnormally expressed, it confers factor-independent growth to hematopoietic cells. In this study, we analyzed the expression levels of PR3 in 113 AML patients. PR3 is highly expressed in AML, mainly in CBF leukemias in which PR3 is not only expressed, but also abnormally localized within the nuclear compartment. Nuclear PR3 results in cleavage of nuclear factor (NF)-κB p65 into an inactive p56 subunit lacking any transcriptional activity. The nuclear localization of PR3 is responsible for increased proliferation, apoptosis arrest and increased sensitivity to high-dose ARA-C. This study provides a new molecular mechanism that is responsible for NF-κB inactivation and increased sensitivity to chemotherapy in CBF leukemias.
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Acknowledgements
This work has been supported by grants from AIRC (Associazione Italiana per la Ricerca sul Cancro), CNR (Progetto Finalizzato Oncologia), MURST-COFIN, AIL (Associazione Italiana contro le Leucemie) and from Regione Piemonte.
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Cilloni, D., Carturan, S., Maffè, C. et al. Proteinase 3 (PR3) gene is highly expressed in CBF leukemias and codes for a protein with abnormal nuclear localization that confers drug sensitivity. Leukemia (2010). https://doi.org/10.1038/leu.2009.207
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DOI: https://doi.org/10.1038/leu.2009.207