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The cleavage product ΔPML–RARα contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells

Abstract

PML–RARα protein, the leukemogenic product of t(15,17) in acute promyelocytic leukemia, is cleaved into a truncated form termed ΔPML–RARα during all-trans retinoic acid (ATRA)-induced differentiation of NB4 cells. ΔPML–RARα is not formed in ATRA differentiation resistant NB4 subclones. As2O3 inhibits ΔPML–RARα formation and differentiation-induction when given in combination with ATRA. Treatment with hexamethylene bisacetamide (HMBA) combined with ATRA enhances ATRA-induced differentiation in ATRA-insensitive NB4-CI and arsenic-resistant NB4/As cells, and is associated with stabilization of PML–RARα protein and increased ΔPML–RARα formation. Unlike forced expression of PML–RARα, forced ΔPML–RARα expression based on an estimated deletion of the N-terminal PML portion does not repress RARE-tk-luc reporter activity mediated by endogenous retinoic acid receptors. The cleavage of PML–RARα is blocked by RARα antagonist Ro-41-5253 and cycloheximide and therefore requires a RARα transactivation-dependent pathway. Proteasome inhibitor MG-132 and caspase inhibitor Z-VAD-FMK do not block ATRA-induced PML–RARα cleavage and differentiation. These data suggest that (a) ATRA treatment induces PML–RARα cleavage by induction of unknown enzymes independent of proteasome- and caspase-mediated pathways; (b) ΔPML–RARα might function differently from both PML–RARα and RARα; (c) failure to cleave PML–RARα and form ΔPML–RARα after ATRA treatment may contribute to ATRA resistance in APL cells.

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Acknowledgements

We thank the following investigators for sharing their cell lines and reagents: Dr. Pierre Chambon (anti-RARα antibody); Dr. Michel Lanotte (NB4 cells); Dr. Carlo Gambacorti-Passerini (NB4.306 cells) and Dr. Wilson H Miller, Jr. (MR-2 and R4 cells). We also appreciate the critical reading by Dr. Rafael Mira-y-Lopez. This work was supported by American Institute for Cancer Research and NIH CA93533.

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Correspondence to Yongkui Jing.

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Jing, Y., Xia, L., Lu, M. et al. The cleavage product ΔPML–RARα contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells. Oncogene 22, 4083–4091 (2003). https://doi.org/10.1038/sj.onc.1206568

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