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Molecular mechanisms of plzf-and pml-raralpha action in acute promyelocytic leukemia


Research objectives and content
Retinoic Acid Receptor-a (RARa) acts as a ligand regulated activator or repressor of gene expression. Recent studies have lead to the identification of co-activator (SRC/TIF family) and co-repressor (N-CoR family) proteins that interact with the RARa and which are thought to mediate these functions. Expression of wild type RARa gene is required for granulocytic differentiation of myeloid cells which is inhibited in Acute Promyelocytic Leukemia (APL). The mechanism(s) by which chromosomal translocation involving RARa gene promote the development of APL are not well understood. I propose to examine whether the development of APL is due, at least in part, to aberrant interactions between RARa fusion proteins, which are expressed as a result of these translocation, and the above negative and positive regulators. I will use in vitro mutagenesis, protein-protein interactions assays and transient transfection experiments to compare interactions of RARa, PML-RARa and PLZF-RARa with N-CoR or the SRC/TIF proteins and to evaluate their significance in the dominant negative function of the above RARa chimeric proteins. Furthermore, I will also explore the possibilities that PML- and/or PLZF-RARa may interfere with the PLZF regulatory pathway by disturbing its normal protein-protein and proteins-DNA interactions. These studies will provide new insights into the role of RARa fusion proteins in leukemogenesis and may also yield important information regarding the function of PLZF, as well as other BTB/POZ-domain zinc-fingers proteins, in control of gene expression during cellular growth and differentiation.
Training content (objective, benefit and expected impact)
The observations on chimeric RARa proteins involved in Leukemogenesis may also have a relevance to the development of novel retinoid ligands that would be useful in treatment of myeloid leukemia. The discovery of novel retinoid ligands that would more effectively inhibit the interaction of the chimeric receptors with N-CoR might lead to a more effective treatment of refractory APL cases.


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