PMID: 9192750Jun 15, 1997Paper

A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RAR alpha mutation.

Blood
W ShaoWilson H Miller

Abstract

The unique t(15;17) of acute promyelocytic leukemia (APL) fuses the PML gene with the retinoic acid receptor alpha (RAR alpha) gene. Although retinoic acid (RA) inhibits cell growth and induces differentiation in human APL cells, resistance to RA develops both in vitro and in patients. We have developed RA-resistant subclones of the human APL cell line, NB4, whose nuclear extracts display altered RA binding. In the RA-resistant subclone, R4, we find an absence of ligand binding of PML-RAR alpha associated with a point mutation changing a leucine to proline in the ligand-binding domain of the fusion PML-RAR alpha protein. In contrast to mutations in RAR alpha found in retinoid-resistant HL60 cells, in this NB4 subclone, the coexpressed RAR alpha remains wild-type. In vitro expression of a cloned PML-RAR alpha with the observed mutation in R4 confirms that this amino acid change causes the loss of ligand binding, but the mutant PML-RAR alpha protein retains the ability to heterodimerize with RXR alpha and thus to bind to retinoid response elements (RAREs). This leads to a dominant negative block of transcription from RAREs that is dose-dependent and not relieved by RA. An unrearranged RAR alpha engineered with this mutation also ...Continue Reading

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