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NFkappaB modulators in a model of glucocorticoid resistant, childhood acute lymphoblastic leukemia
Lindsay Nicholson1, Andrew G Hall, Christopher P Redfern
1Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Tyne and Wear NE2 4HH, UK.
Abstract:
Glucocorticoids (GCs) are pivotal agents in the treatment of childhood acute lymphoblastic leukaemia (ALL) but the molecular basis of GC-resistance remains unclear. Expression-array studies have shown that commonly upregulated genes associated with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and IkappaBalpha, which all negatively interact with components of the pro-survival NFkappaB pathway and therefore may be critical determinants of GC-sensitivity. We have investigated these regulators and their effect on NFkappaB activity in GC-resistant descendents of the B-lineage ALL cell line, PreB 697. We show that while differential up regulation of the modulators (GILZ, GR and IkappaBalpha) was demonstrated in GC-sensitive compared to GC-resistant sub-lines, this was not coupled with altered nuclear translocation or functionality of the RelA, p50 or c-Rel subunits of NFkappaB. Thus, GC-resistance in the PreB 697 cell line model is not mediated by NFkappaB, however further investigation of the impact of these GC-sensitive associated proteins on other survival pathways, such as the RAS-RAF-MEK-ERK pathway, is warranted.
Insights
Glucocorticoid (GC) resistance in childhood acute lymphoblastic leukemia (ALL) is not due to the NFkappaB pathway. Key GC-sensitivity regulators like GILZ and GR do not alter NFkappaB activity in resistant ALL cells.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Glucocorticoids (GCs) are crucial for treating childhood acute lymphoblastic leukemia (ALL).
- The molecular mechanisms underlying GC resistance in ALL are not fully understood.
- Genes like GR, GILZ, and IkappaBalpha, which interact with the NFkappaB pathway, are linked to GC sensitivity.
Purpose of the Study:
- To investigate the role of GC-sensitive regulators (GR, GILZ, IkappaBalpha) in GC resistance in ALL.
- To determine if altered NFkappaB pathway activity mediates GC resistance in the PreB 697 ALL cell line model.
Main Methods:
- Comparative analysis of gene expression in GC-sensitive versus GC-resistant ALL sub-lines.
- Assessment of NFkappaB pathway components (RelA, p50, c-Rel) nuclear translocation and function.
Main Results:
- Differential upregulation of GILZ, GR, and IkappaBalpha was observed in GC-sensitive ALL sub-lines compared to resistant ones.
- Despite differential expression of these regulators, NFkappaB pathway activity, including nuclear translocation and function of its subunits, remained unaltered in GC-resistant cells.
- The study model (PreB 697 cell line) did not show NFkappaB-mediated GC resistance.
Conclusions:
- NFkappaB pathway is not the mediator of GC resistance in the PreB 697 ALL cell line model.
- Further research is needed to explore the impact of GC-sensitive proteins on other survival pathways, such as the RAS-RAF-MEK-ERK pathway, in ALL GC resistance.
