Leukemic transformation by the APL fusion protein PRKAR1A-RAR{alpha} critically depends on recruitment of RXR{alpha} - Archive ouverte HAL
Article Dans Une Revue Blood Année : 2010

Leukemic transformation by the APL fusion protein PRKAR1A-RAR{alpha} critically depends on recruitment of RXR{alpha}

Jihui J. Qiu
  • Fonction : Auteur
Xiaoxi Lu
  • Fonction : Auteur
Bernd Zeisig
  • Fonction : Auteur
Zhigui Ma
  • Fonction : Auteur
Xun Cai
  • Fonction : Auteur
Saijuan Chen
  • Fonction : Auteur
David J. Tweardy
  • Fonction : Auteur
Chi Wai Eric So
  • Fonction : Auteur
Shuo Dong
  • Fonction : Auteur

Résumé

PRKAR1A (R1A)-retinoic acid receptor-alpha (R1A-RARalpha) is the sixth RARalpha-containing fusion protein in acute promyelocytic leukemia (APL). Using the murine bone-marrow retroviral transduction/transformation assay, we showed that R1A-RARalpha fusion protein could transform bone-marrow progenitor/stem cells. In gel-shift assays, R1A-RARalpha was able to bind to a panel of retinoic acid response elements both as a homodimer and as a heterodimer with RXRalpha, and demonstrated distinct DNA-binding characteristics compared with wild-type RARalpha/RXRalpha or other X-RARalpha chimeric proteins. The ratio of R1A-RARalpha to RXRalpha proteins affected the retinoic acid response element interaction pattern of R1A-RARalpha/RXRalpha complexes. Studies comparing R1A-RARalpha with R1A-RARalpha(DeltaRIIa) demonstrated that the RIIa protein interaction domain located within R1A was responsible for R1A-RARalpha homodimeric DNA binding and interaction with wild-type R1A protein. However, the RIIa domain was not required for R1A-RARalpha-mediated transformation because its deletion in R1A-RARalpha(DeltaRIIa) did not compromise its transformation capability. In contrast, introduction of point mutations within the RARalpha portion of either R1A-RARalpha or R1A-RARalpha(DeltaRIIa), previously demonstrated to eliminate RXRalpha interaction or treatment of transduced cells with RXRalpha shRNA or a RXRalpha agonist, reduced transformation capability. Thus, leukemic transformation by APL fusion protein PRKAR1A-RARalpha is critically dependent on RXRalpha, which suggests RXRalpha is a promising target for APL.
Fichier non déposé

Dates et versions

hal-04029370 , version 1 (14-03-2023)

Identifiants

Citer

Jihui J. Qiu, Xiaoxi Lu, Bernd Zeisig, Zhigui Ma, Xun Cai, et al.. Leukemic transformation by the APL fusion protein PRKAR1A-RAR{alpha} critically depends on recruitment of RXR{alpha}. Blood, 2010, 115 (3), pp.643-652. ⟨10.1182/blood-2009-07-232652⟩. ⟨hal-04029370⟩
9 Consultations
0 Téléchargements

Altmetric

Partager

More