PIC-1/SUMO-1-modified PML-retinoic acid receptor alpha mediates arsenic trioxide-induced apoptosis in acute promyelocytic leukemia

Fusion proteins involving the retinoic acid receptor alpha (RAR alpha) and PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemia (APL). APLs with PML-RAR alpha or PLZF-RAR alpha fusion protein di ffer only in their response to retinoic acid (RA) treatment: the t(15;17) ( PML-RAR alpha-positive) APL blasts are sensitive to RA in vitro, and patien ts enter disease remission after RA treatment, while those with t(11;17) (P LZF-RAR alpha-positive) APLs do not. Recently it has been shown that comple te remission can be achieved upon treatment with arsenic trioxide (As2O3) i n PML-RAR alpha-positive APL, even when the patient has relapsed and the di sease 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) As 2O3 induces apoptosis only in cells expressing the PML-RAR alpha, not the P LZF-RAR alpha, fusion protein; (ii) PML-RAR alpha, is partially modified by covalent linkage with a PIC-1/SUMO-1-like protein prior to As2O3 treatment , whereas PLZF-RAR alpha is not; (iii) As2O3 treatment induces a change in the modification pattern of PML-RAR alpha toward highly modified forms; (iv ) redistribution of PML nuclear bodies (PML-NBs) upon As2O3 treatment is ac companied by recruitment of PIC-1/SUMO-1 into PML-NBs, probably due to hype rmodification of both PML and PML-RAR alpha; (v) As2O3-induced apoptosis is independent of the DNA binding activity located in the RAR alpha portion o f the PML-RAR alpha fusion protein; and (vi) the apoptotic process is bcl-2 and caspase 3 independent and is blocked only partially by a global caspas e inhibitor. Taken together, these data provide novel insights into the mec hanisms involved in As2O3-induced apoptosis in APL and predict that treatme nt of t(11;17) (PLZF-RAR alpha-positive) APLs with As2O3 will not be succes sful.