Modulation of PML and PMLRARa genes

The vast majority of cases of APL are characterized by the t(15; 17) translocation. This translocation generates a fusion between the PML (promyelocytic leukemic) gene and the RARa (retinoic acid receptor alpha) gene, which encodes a transcription factor.23 PML is a tumor suppressor involved in complex functions including growth arrest and apoptosis induction. The PML RARa fusion protein inhibits PML-dependent apoptotic pathways and blocks myeloid differentiation by direct transcriptional inhibition of retinoic acid (RA) target genes.24 The block in myeloid differentiation by PML-RARa can be released by treatment with pharmacological levels of RA, providing the basis for ATRA therapy for APL. ATRA is used in treatment of APL to induce differentiation of leukemic promyelocytes.25 As2O3 has been proposed as an alternative to treatment with ATRA, because it can induce complete remission in both ATRA-sensitive and ATRA-resistant APL patients.26 The anti-leukemic effects of As2O3 were mediated by its ability to induce the relocation and degradation of PML, and the degradation of PML-RARa in APL cells.27 29 Sequence analysis of the PML gene has shown the presence of a cysteine-rich region that may be a potential site for interaction with trivalent arsenic. Evidence suggested that in APL patients, RA induces differentiation, whereas arsenic induces both a partial differentiation and apoptosis. Their mechanisms of action are believed to be distinct, but both appear to induce degradation of the PML-RARa fusion protein and their effects may be synergistic.30

Although both RA and arsenic induce degradation of PML-RARa, several differences in their action on APL cells have been reported. In vitro, ATRA induces differentiation of APL along a granulocytic pathway, whereas, as identified from both in vitro and in vivo studies, arsenic induces dual differentiation and apoptosis of APL at low concentrations (0.0-0.5 mM), and only apoptosis at no ^ 1 ^ ^

high clinically achievable concentrations (1-2 mM). " In APL cells sensitive to ATRA, in vitro treatment with arsenic antagonizes ATRA-induced differentiation, whereas treatment with ATRA decreases arsenic-induced apoptosis.28,34 However, in several models of cells resistant to differentiation by ATRA alone, sub-apoptotic concentrations of arsenic can synergize with ATRA to induce differentiation.11,34 Gianni etal.35 isolated an As2O3-resistant NB4 subline (NB4-AsR). These cells failed to undergo apoptosis, but maintained the partial differentiation response to arsenic, whereas ATRA-triggered differentiation and apoptosis were accelerated in the As2O3-treated NB4-AsR cells. In a clinical study, As2O3 was found able to induce differentiation in patients with APL who have relapsed after ATRA treatment.36 This is consistent with a previous in vitro study suggesting that APL cell growth arrest and differentiation could occur without PML RARa degradation,37 and that preservation of the malignant phenotype may not require a detectable expression of the fusion protein in some APL clones.38

One potential important difference in the mechanism by which As2O3 and ATRA induce degradation of the PML-RARa fusion protein is that As2O3 targets the PML portion of the protein, whereas ATRA targets the RARa.27 In non-APL cells, arsenic accelerates the targeting of PML onto nuclear bodies (NB) and induces degradation of the PML protein.27 PML has been shown to suppress growth39 and induce apoptosis.40 As2O3 alters the traffic of PML proteins, enhancing their association with NB as well as their apoptotic proper-ties.27,41 NB/PML localization appears to be required for the arsenic-induced anti-proliferative and apoptotic effect. Furthermore, As2O3 increases covalent modifications of PML by SUMO-1, a small ubiquitin-like protein. The SUMO-1 polymodified forms of PML are compartmentalized entirely in the PML-NBs in non-APL cells, whereas the unmodified form of PML is found in the soluble nucleoplasmic fraction.41,42

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