Schematic representations of the PML/RARα mutations.

(A) Schematic of the LBD PML/RARα mutations identified in RA-resistant APL cell lines (numbers 1-5) and relapsed patients (numbers 6-11). The alignment of TRβ LBD and the PML/RARα E-domain by sequence homology indicates that the mutations in RA-resistant APL patients and cell lines cluster in accordance with the regions in resistance to thyroid hormone (RTH) syndrome denoted as I, II, and III. Numbers 6, 8, 9, 10, and 11 indicate the mutations in the LBD PML/RARα of RA-resistant APL patients evaluated in this study. The position of the mutations is described with reference to normal amino acid sequence of RARα1.32 DBD indicates DNA-binding domain; LBD, ligand-binding domain; DD, dimerization domain; AD, activation domain. (B) A 3-dimensional model of the LBD of the holo-RAR, showing the locations of the evaluated mutants. The structure of the LBD is based on x-ray crystal structure analysis of the liganded RARγ.45,46