Mutations in the E-domain of RARα portion of the PML/RARα chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia

Masue Imaizumi, Hoshiro Suzuki, Miyako Yoshinari, Atsushi Sato, Toshiaki Saito, Akira Sugawara, Shigeru Tsuchiya, Yoshiro Hatae, Takeo Fujimoto, Akira Kakizuka, Tasuke Konno, Kazuie Linuma

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)

Abstract

The binding of all-trans retinoic acid (ATRA) to the ligand-binding region in the E-domain of retinoic acid receptor-α (RARα) modifies the transcriptional activity of RARα protein. ATRA probably induces differentiation of acute promyelocytic leukemia (APL) cells by binding to the E-domain of the RARα portion (RARα/E-domain) of PML/RARα chimeric protein. Therefore, molecular alteration in the RARα/E-domain of the chimeric gene is one mechanism by which patients with APL may acquire resistance to ATRA therapy. In this study using reverse transcription-polymerase chain reaction and single-strand conformation polymorphism, DNA segments amplified from the RARα/E-domain in fresh APL cells of 23 APL patients (8 males and 15 females from 4 to 76 years of age) were screened for mutations. Of those patients, 3 patients (1 with de novo and 2 with relapse) had clinical resistance to ATRA therapy. We found mutations in the RARα/E-domain of PML/RARα chimeric gene exclusively in the 2 patients who exhibited ATRA-resistance at relapse, whereas the mutations were not detected at their initial onset. Interestingly, these patients received a prolonged or intermittent administration of ATRA before relapse with ATRA-resistance. The mutations lead to the change of amino acid in the ligand-binding region of RARα/E- domain, Arg272Gln, or Met297Leu according to the amino acid sequence of RARα, respectively. Further study demonstrated that the in vitro ligand- dependent transcriptional activity of the mutant PML/RARα protein was significantly decreased as compared with that of wild-type PML/RARα. These findings suggest that mutations in the RARα/E-domain of the PML/RARα chimeric gene may confer clinical resistance to ATRA therapy in patients with APL.

Original languageEnglish
Pages (from-to)374-382
Number of pages9
JournalBlood
Volume92
Issue number2
DOIs
Publication statusPublished - 1998 Jul 15
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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