Missense mutations in the PML/RAR alpha ligand binding domain in ATRA-resistant As2O3 sensitive relapsed acute promyelocytic leukemia

Citation
R. Marasca et al., Missense mutations in the PML/RAR alpha ligand binding domain in ATRA-resistant As2O3 sensitive relapsed acute promyelocytic leukemia, HAEMATOLOG, 84(11), 1999, pp. 963-968
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
HAEMATOLOGICA
ISSN journal
0390-6078 → ACNP
Volume
84
Issue
11
Year of publication
1999
Pages
963 - 968
Database
ISI
SICI code
0390-6078(199911)84:11<963:MMITPA>2.0.ZU;2-E
Abstract
Background and Objectives. Acute promyelocytic leukemia is characterized by the chromosomal translocation t(15;17) which yields the fusion product PML /RAR alpha. Art-trans retinoic acid probably induces differentiation of aty pical promyelocytes and clinical remission in APL patients by binding to th e ligand binding domain (LBD) of the RAR alpha portion of the PML-RAR alpha chimeric protein. Structural alterations of the LED of the PML/RAR alpha h ave been revealed in ATRA-resistant APL cell lines and in a few APL patient s with acquired clinical resistance to ATRA therapy. Two APL relapsed patie nts with clinical resistance to ATRA therapy were evaluated for the presenc e of nucleotide mutations in the LED of PML/RAR alpha gene and then treated with arsenic trioxide (As2O3). Design and Methods. DNA fragments from the LED of the PML/RAR alpha: chimer ic transcript were obtained by reverse-transcribed polymerase chain reactio n. Direct sequencing was performed by an unambiguous bidirectional automati c analysis. Samples representative of APL onset and relapse were analyzed f rom both patients. Results. In both patients, at the ATRA-resistant relapse, a missense point mutation in the LED of the PML/RAR alpha gene was found. The mutations, abs ent at APL onset, led to an Arg272Gln and to an Arg276Trp amino acid substi tution, according to the sequence of the RAR alpha protein. Both patients h ad complete clinical and hematologic remission after treatment with As2O3. Interpretation and Conclusions. LED missense mutations appear to be a signi ficant mechanism of acquired ATRA-resistance in vivo, closely related to cl inical APL relapse. The two cases reported here provide the first in vivo e vidence of Apt, relapsed patients, who have become ATRA-resistant for molec ular reasons, being sensitive to arsenic trioxide. (C) 1999, Ferrata Storti Foundation.