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Molecular and Cellular Biology, July 1999, p. 5170-5178, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

PIC-1/SUMO-1-Modified PML-Retinoic Acid Receptor alpha  Mediates Arsenic Trioxide-Induced Apoptosis in Acute Promyelocytic Leukemia

Thomas Sternsdorf,1 Elena Puccetti,2 Kirsten Jensen,1 Dieter Hoelzer,2 Hans Will,1 Oliver Gerhard Ottmann,2 and Martin Ruthardt2,*

Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität, D-20251 Hamburg,1 and Med. Klinik III/Abtl. Hämatologie, Johann Wolfgang Goethe-Universität, D-60590 Frankfurt,2 Germany

Received 30 November 1998/Returned for modification 12 February 1999/Accepted 14 April 1999

Fusion proteins involving the retinoic acid receptor alpha  (RARalpha ) and PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemia (APL). APLs with PML-RARalpha or PLZF-RARalpha fusion protein differ only in their response to retinoic acid (RA) treatment: the t(15;17) (PML-RARalpha -positive) APL blasts are sensitive to RA in vitro, and patients enter disease remission after RA treatment, while those with t(11;17) (PLZF-RARalpha -positive) APLs do not. Recently it has been shown that complete remission can be achieved upon treatment with arsenic trioxide (As2O3) in PML-RARalpha -positive APL, even when the patient has relapsed and the disease is RA resistant. This appears to be due to apoptosis induced by As2O3 in the APL blasts by poorly defined mechanisms. Here we report that (i) As2O3 induces apoptosis only in cells expressing the PML-RARalpha , not the PLZF-RARalpha , fusion protein; (ii) PML-RARalpha is partially modified by covalent linkage with a PIC-1/SUMO-1-like protein prior to As2O3 treatment, whereas PLZF-RARalpha is not; (iii) As2O3 treatment induces a change in the modification pattern of PML-RARalpha toward highly modified forms; (iv) redistribution of PML nuclear bodies (PML-NBs) upon As2O3 treatment is accompanied by recruitment of PIC-1/SUMO-1 into PML-NBs, probably due to hypermodification of both PML and PML-RARalpha ; (v) As2O3-induced apoptosis is independent of the DNA binding activity located in the RARalpha portion of the PML-RARalpha fusion protein; and (vi) the apoptotic process is bcl-2 and caspase 3 independent and is blocked only partially by a global caspase inhibitor. Taken together, these data provide novel insights into the mechanisms involved in As2O3-induced apoptosis in APL and predict that treatment of t(11;17) (PLZF-RARalpha -positive) APLs with As2O3 will not be successful.

* Corresponding author. Mailing address: Med. Klinik III/Abtl. Hämatologie, Klinikum der J. W. Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany. Phone: 49-69-6301-6129. Fax: 49-69-6301-6131. E-mail: ruthardt{at}em.uni-frankfurt.de.

Molecular and Cellular Biology, July 1999, p. 5170-5178, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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