Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein.

Content Provider	Semantic Scholar
Author	Nervi, Clara Ferrara, Fabiana Fosca Fanelli, M. Rippo, Maria Rita Tomassini, Barbara Ferrucci, Pier Francesco Ruthardt, Martin Gelmetti, Vania Passerini, Carlo Gambacorti‐ Diverio, Daniela Grignani, Francesco Pelicci, Pier Giuseppe Testi, Roberto
Copyright Year	1998
Abstract	All-trans-retinoic acid (RA) treatment induces morphological remission in acute promyelocytic leukemia (APL) patients carrying the t(15;17) and expressing the PML/RARalpha product by inducing terminal differentiation of the leukemic clone. RA treatment induces downregulation of PML/RARalpha and reorganization of the PML-nuclear bodies. These events have been proposed to be essential for the induction of APL cell differentiation by RA. Here, we show that in the APL-derived NB4 cell line as well as in myeloid precursor U937 cells expressing the PML/RARalpha (U937/PR9) and in blasts from APL patients, the PML/RARalpha fusion protein is cleaved by a caspase 3-like activity induced by RA treatment. In fact, a caspase 3-like activity is detectable in PML/RARalpha expressing cells after RA treatment, and selective caspase inhibitor peptides are able to prevent the RA-induced degradation of the fusion protein in vivo and in vitro. Using recombinant caspases and PML/RARalpha deletion mutants we mapped a caspase 3 cleavage site (Asp 522) within the alpha-helix region of the PML component of the fusion protein. The extent of PML/RARalpha cleavage directly correlates with the ability of RA to restore the normal PML nuclear bodies (NBs) pattern. However, RA-induced differentiation is not prevented by the persistence of the fusion product and occurs in the absence of normally structured PML NBs. These results indicate that PML/RARalpha is directly involved in conferring RA sensitivity of APL cells and that the RA-induced reassembly of PML NBs is the consequence of the disappearance of PML/RARalpha.
File Format	PDF HTM / HTML
DOI	10.1182/blood.V92.7.2244.2244_2244_2251
PubMed reference number	9746761
Journal	Medline
Volume Number	92
Issue Number	7
Alternate Webpage(s)	http://www.bloodjournal.org/content/bloodjournal/92/7/2244.full.pdf?sso-checked=true
Alternate Webpage(s)	https://doi.org/10.1182/blood.V92.7.2244.2244_2244_2251
Journal	Blood
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article