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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2244-2251
Caspases Mediate Retinoic Acid-Induced Degradation of the Acute
Promyelocytic Leukemia PML/RAR Fusion Protein
Clara Nervi,
Fabiana F. Ferrara,
Mirco Fanelli,
Maria Rita Rippo,
Barbara Tomassini,
Pier Francesco Ferrucci,
Martin Ruthardt,
Vania Gelmetti,
Carlo Gambacorti-Passerini,
Daniela Diverio,
Francesco Grignani,
Pier Giuseppe Pelicci, and
Roberto Testi
From the Dipartimento di Istologia ed Embriologia Medica and
Dipartimento di Biotecnologie Cellulari e Ematologia, University of
Rome "La Sapienza," Rome; the European Institute of Oncology,
Department of Experimental Oncology, Milan; the Dipartimento di
Medicina Sperimentale e Scienze Biochimiche, University of Rome "Tor
Vergata," Rome; Istituto di Medicina Interna e Scienze Oncologiche,
Perugia University, Perugia; the Division of Experimental Oncology D,
Istituto Nazionale Tumori, Milan, Italy; and the Department of
Hematology, J.-W. Goethe University, Frankfurt, Germany.
All-trans-retinoic acid (RA) treatment induces morphological
remission in acute promyelocytic leukemia (APL) patients carrying the
t(15;17) and expressing the PML/RAR product by inducing terminal differentiation of the leukemic clone. RA treatment induces
downregulation of PML/RAR 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/RAR (U937/PR9) and in blasts from APL patients,
the PML/RAR 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/RAR 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/RAR deletion mutants we mapped a caspase 3 cleavage site (Asp 522) within the -helix
region of the PML component of the fusion protein. The extent of
PML/RAR 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/RAR 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/RAR.
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