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

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