Type II Nuclear receptors (T2NRs) are ligand activated transctription factors that require heterodimerization with the retinoid X receptor (RXR), to bind chromatin and drive gene expression. Here, RXR is a limiting factor because a common pool of this protein is shared among all the different T2NRs (i.e. there is competition between individual T2NRs for RXR). In acute promyelotic leukemia (APL), a chromosomal translocation results in fusion of one of the T2NR- retinoic acid receptor-alpha (RARA) to various other proteins.
Different mechanisms have been proposed to be the cause of oncogenesis in APL:
1. Disrupted competition between T2NR for RXR ( for example; fusion proteins may compete RXR away from wild-type RARA leading to oncogenic inactivation of wildtype RARA; thus, impairing its ability to regulate target genes)
2. Aberrant high affinity of RARA fusion proteins to coregulators (co-repressors/co-activators) disrupting transcription of key genes involved in myeloid differentiaiton.
3. Mislocalization of wild-type N protein in N-RARA fusion proteins leading to myeloid differentiation block.
I will use a combination of biochemical assays, imaging techniques like single particle tracking (SPT) and genomic tools to investigate the underlying mechanism of action of RARA-fusion proteins in APL disease.