Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity

Kent Robertson, Babak Emami, Steven J. Collins

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

Retinoic acid (RA) induces granulocytic differentiation of acute promyelocytic leukemia (APL) cells and is a useful therapeutic agent for patients with this disease. In the HL-60 promyelocytic leukemia cell line, this RA-induced granulocytic differentiation appears to be directly mediated through the RA receptor (RAR-α). We have previously identified a mutant subclone of HL-60 (designated HL-60R) that exhibits relative resistance to RA and that harbors RA receptors with markedly reduced affinity for RA. In the present study, we have now identified the genetic basis for this aberrant RA receptor activity. DNA sequencing of polymerase chain reaction-amplified cDNA products corresponding to the RAR-α ligand-binding domain shows a point mutation in RAR-α codon 411 in this mutant HL-60R subclone. This specific C → T mutation generates a termination codon resulting in the truncation of 52 amino acids at the COOH terminal end of RAR-α. In cotransfection studies, expression vectors harbor-ing this mutated RAR-α exhibit dominant negative activity with respect to the trans-activating function of the normal RAR-α. Although our observations are limited to HL-60 cells, similar RA receptor mutations might play an important role in the acquisition of RA resistance in RA-treated APL patients.

Original languageEnglish (US)
Pages (from-to)1885-1889
Number of pages5
JournalBlood
Volume80
Issue number8
StatePublished - Oct 15 1992
Externally publishedYes

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Retinoic Acid Receptors
Ports and harbors
Tretinoin
Point Mutation
Ligands
Acute Promyelocytic Leukemia
Acid resistance
Mutation
Terminator Codon
HL-60 Cells
Polymerase chain reaction
Proxy
DNA-Directed DNA Polymerase
DNA Sequence Analysis
Codon
Leukemia
Complementary DNA
Cells
Amino Acids
Cell Line

ASJC Scopus subject areas

  • Hematology

Cite this

Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity. / Robertson, Kent; Emami, Babak; Collins, Steven J.

In: Blood, Vol. 80, No. 8, 15.10.1992, p. 1885-1889.

Research output: Contribution to journalArticle

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