Abstract
Acute lymphoblastic leukemia (ALL) is one of the most common forms of malignancy that occurs in lymphoid progenitor cells, particularly in children. Synthetic steroid hormones glucocorticoids (GCs) are widely used as part of the ALL treatment regimens due to their apoptotic function, but their use also brings about various side effects and drug resistance. The identification of the molecular differences between the GCs responsive and resistant cells therefore are essential to decipher such complexity and can be used to improve therapy. However, the emerging picture is complicated as the activities of genes and proteins involved are controlled by multiple factors. By adopting the systems biology framework to address this issue, we here integrated the available knowledge together with experimental data by building a series of mathematical models. This rationale enabled us to unravel molecular interactions involving c-Jun in GC induced apoptosis and identify Ets-related gene (Erg) as potential biomarker of GC resistance. The results revealed an alternative possible mechanism where c-Jun may be an indirect GR target that is controlled via an upstream repressor protein. The models also highlight the importance of Erg for GR function, particularly in GC sensitive C7 cells where Erg directly regulates GR in agreement with our previous experimental results. Our models describe potential GR-controlled molecular mechanisms of c-Jun/Bim and Erg regulation. We also demonstrate the importance of using a systematic approach to translate human disease processes into computational models in order to derive information-driven new hypotheses.
Highlights
Acute lymphoblastic leukemia (ALL) refers to a cancer of T- or Blymphoid progenitor cells, which is found to be the most common childhood malignancy (Pui et al, 2008)
MODELING glucocorticoid receptor (GR) REGULATION OF BIM VIA C-JUN ACTIVATION IN GC SENSITIVE C7 CELLS GR induced apoptosis occurs through an intrinsic mitochondria dependent pathway via regulation of BCL-2 family proteins
Compared to the known direct GR target BclXL, both c-Jun and Bim were induced by GR much later, as a dramatic induction was observed between 6–10 h, suggesting a potential delayed and indirect GR induced activation mechanism (Chen et al, 2010)
Summary
Acute lymphoblastic leukemia (ALL) refers to a cancer of T- or Blymphoid progenitor cells, which is found to be the most common childhood malignancy (Pui et al, 2008). Glucocorticoids (GC) have been used as part of the treatment of many diseases including ALL, owing to their anti-inflammatory and anti-cancerous actions (Schaaf and Cidlowski, 2002). One of the main causes for resistance to GC is the defective signaling of GC to target genes in relation to apoptosis. The principle of GC therapy in ALL is GC induced apoptosis, whereby GC activates the glucocorticoid receptor (GR) that upon hormone binding translocates to the nucleus and targets the apoptosis mediating family, the B-cell lymphoma 2 (Bcl-2). The Bcl-2 member Bim is known to be an essential initiator of apoptosis (Wang et al, 2003; Abrams et al, 2004; Ploner et al, 2007; Zhao et al, 2011) and an indirect GR target (Wang et al, 2003). The GR regulation of Bim in ALL is not fully defined; it was reported that c-Jun may be a potential candidate for targeting Bim
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
