Targeting of PML/RARalpha is lethal to retinoic acid-resistant promyelocytic leukemia cells.

Acute promyelocytic leukemia (APL) cells, containing the t(15;17) rearrangement, express the fusion protein, PML/RARalpha. Clinically, patients respond to all-trans retinoic acid (ATRA) through complete remissions associated with myeloid maturation of leukemic cells. This clinical ATRA response of APL is linked to PML/RARalpha expression. Unfortunately, these remissions are transient and relapsed APL is often ATRA-resistant. The role PML/RARalpha plays in the growth and maturation of these APL cells with acquired ATRA resistance has not been fully explored. This study uses an ATRA-resistant NB4 cell line (NB4-R1) to investigate the contribution of PML/RARalpha expression to ATRA resistance. Targeting of PML/RARalpha in NB4-R1 cells was undertaken using two approaches: homologous recombination and hammerhead ribozyme-mediated cleavage. Reducing PML/RARalpha protein in NB4-R1 cells rendered these cells more sensitive to ATRA. These cells were growth-inhibited in ATRA, apoptosis was induced, and there was no apparent signaling of differentiation. Sequence analysis identified a mutation in the ligand binding domain (LBD) of the RARalpha portion of PML/RARalpha. Results show that these retinoid-resistant NB4 cells require persistent PML/RARalpha expression for leukemic cell growth. Taken together, these findings can account for why these cells do not respond to ATRA and how reduction of PML/RARalpha abrogates the antiapoptotic effect it confers to these leukemic cells.

Nason-Burchenal K ，Allopenna J ，Bègue A ，Stéhelin D ，Dmitrovsky E ，Martin P ... -  《BLOOD》

Growth suppression of acute promyelocytic leukemia cells having increased expression of the non-rearranged alleles: RAR alpha or PML.

Ahn MJ ，Nason-Burchenal K ，Moasser MM ，Dmitrovsky E ... -  《ONCOGENE》

Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia.

Guidez F ，Ivins S ，Zhu J ，Söderström M ，Waxman S ，Zelent A ... -  《BLOOD》

cAMP signalling is decisive for recovery of nuclear bodies (PODs) during maturation of RA-resistant t(15;17) promyelocytic leukemia NB4 cells expressing PML-RAR alpha.

Duprez E ，Lillehaug JR ，Naoe T ，Lanotte M ... -  《ONCOGENE》

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

Imaizumi M ，Suzuki H ，Yoshinari M ，Sato A ，Saito T ，Sugawara A ，Tsuchiya S ，Hatae Y ，Fujimoto T ，Kakizuka A ，Konno T ，Iinuma K ... -  《BLOOD》