NTU Undergraduates' research April 2014 - Biosciences | Page 140

Role of NF-кB in Leukaemia Cells Proliferation
Ana Domostegui Fernández (N0544966)

Abstract
The nuclear factor NF-кB is one of the targets of the phosphoinositide 3-kinase pathway (PI3K)/AKT
pathway. NF-кB belongs to a family of transcription factors involved in survival, differentiation and
proliferation of the cells. Therefore, the deregulation of this pathway is linked to tumour development.
Majority of chronic myeloid leukaemias (CML) have been found that carry a mutation in the BCR gene,
which is fused with the ABL proto-oncogene. This reciprocal translocation results in the production of
the BCR-ABL oncoprotein, whose kinase domain constitutively active triggers the upregulation of the
PI3K/AKT pathway and the subsequent activation of NF-кB.
Here, the effect of a BCR-ABL inhibitor, Imatinib mesylate, is investigated. First, the proliferation of a
BCR-ABL positive cell line (KU812) is studied through an assay called Neutral Red Assay. It is found that
Imatinib inhibits the proliferation of the CML cells in a dose-dependent manner. Moreover, the role
of NF-кB is analysed by Western blot in both nuclear and cytoplasmic extracts. Imatinib inhibits NF-кB
translocation to the nucleus and enhances apoptosis in BCR-ABL positive cells. These findings suggest
that Imatinib is a potent inhibitor of CML cells proliferation through the blockade of the PI3K/AKT
signalling pathway, which is responsible for the activation of NF-кB. However, additional mechanisms
might trigger NF-кB activation and explain, at least in part, the resistance of some CML cells to
Imatinib.
Keywords: Chronic Myeloid Leukaemia, BCR-ABL, Imatinib, Apoptosis, p65/Rel A, TK Inhibitors.