MUTATIONS IN THE E-DOMAIN OF RAR-ALPHA PORTION OF THE PML RAR-ALPHA CHIMERIC GENE MAY CONFER CLINICAL RESISTANCE TO ALL-TRANS-RETINOIC ACIDIN ACUTE PROMYELOCYTIC LEUKEMIA/
M. Imaizumi et al., MUTATIONS IN THE E-DOMAIN OF RAR-ALPHA PORTION OF THE PML RAR-ALPHA CHIMERIC GENE MAY CONFER CLINICAL RESISTANCE TO ALL-TRANS-RETINOIC ACIDIN ACUTE PROMYELOCYTIC LEUKEMIA/, Blood, 92(2), 1998, pp. 374-382
The binding of all-trans retinoic acid (ATRA) to the ligand-binding re
gion in the E-domain of retinoic acid receptor-alpha (RAR alpha) modif
ies the transcriptional activity of RAR alpha protein. ATRA probably i
nduces differentiation of acute promyelocytic leukemia (APL) cells by
binding to the E-domain of the RAR alpha portion (RAR alpha/E-domain)
of PML/RAR alpha chimeric protein. Therefore, molecular alteration in
the RARa/E-domain of the chimeric gene is one mechanism by which patie
nts with APL may acquire resistance to ATRA therapy. In this study usi
ng reverse transcription polymerase chain reaction and single-strand c
onformation polymorphism, DNA segments amplified from the RAR alpha/E-
domain in fresh APL cells of 23 APL patients (8 males and 15 females f
rom 4 to 76 years of age) were screened for mutations. Of those patien
ts, 3 patients (1 with de novo and 2 with relapse) had clinical resist
ance to ATRA therapy. We found mutations in the RAR alpha/E-domain of
PML/RAR alpha chimeric gene exclusively in the 2 patients who exhibite
d ATRA-resistance at relapse, whereas the mutations were not detected
at their initial onset. Interestingly, these patients received a prolo
nged or intermittent administration of ATRA before relapse with ATRA-r
esistance. The mutations lead to the change of amino acid in the ligan
d-binding region of RAR alpha/E domain, Arg272Gln, or Met297Leu accord
ing to the amino acid sequence of RAR alpha, respectively. Further stu
dy demonstrated that the in vitro ligand-dependent transcriptional act
ivity of the mutant PML/RAR alpha protein was significantly decreased
as compared with that of wild type PML/RAR alpha. These findings sugge
st that mutations in the RAR alpha/E domain of the PML/RAR alpha chime
ric gene may confer clinical resistance to ATRA therapy in patients wi
th APL. (C) 1998 by The American Society of Hematology.