A Retinoid - Resistant Acute Promyelocytic Leukemia Subclone Expresses a Dominant Negative PML - RAR a Mutation

The unique t(15;17) of acute promyelocytic leukemia (APL) retinoid response elements (RAREs). This leads to a dominant negative block of transcription from RAREs that is dosefuses the PML gene with the retinoic acid receptor a (RARa) gene. Although retinoic acid (RA) inhibits cell growth and dependent and not relieved by RA. An unrearranged RARa engineered with this mutation also lost ligand binding and induces differentiation in human APL cells, resistance to RA develops both in vitro and in patients. We have developed inhibited transcription in a dominant negative manner. We then found that the mutant PML-RARa selectively alters regRA-resistant subclones of the human APL cell line, NB4, whose nuclear extracts display altered RA binding. In the ulation of gene expression in the R4 cell line. R4 cells have lost retinoid-regulation of RXRa and RARb and the RA-inRA-resistant subclone, R4, we find an absence of ligand binding of PML-RARa associated with a point mutation changing duced loss of PML-RARa protein seen in NB4 cells, but retain retinoid-induction of CD18 and CD38. Thus, the R4 cell line a leucine to proline in the ligand-binding domain of the fusion PML-RARa protein. In contrast to mutations in RARa provides data supporting the presence of an RARa-mediated pathway that is independent from gene expression induced found in retinoid-resistant HL60 cells, in this NB4 subclone, the coexpressed RARa remains wild-type. In vitro expresor repressed by PML-RARa. The high level of retinoid resistance in vitro and in vivo of cells from some relapsed APL sion of a cloned PML-RARa with the observed mutation in R4 confirms that this amino acid change causes the loss of patients suggests similar molecular changes may occur clinically. ligand binding, but the mutant PML-RARa protein retains the ability to heterodimerize with RXRa and thus to bind to q 1997 by The American Society of Hematology.