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Significance Acute promyelocytic leukemia (APL) is a model for oncoprotein-targeted therapy because induced degradation of the promyelocytic leukemia protein–retinoic acid receptor (PML–RAR) fusion protein by retinoic acid and arsenic trioxide essentially eradicates the disease. Here we elucidate a previously unidentified feature of the PML domain, demonstrating that inhibition of cellular senescence may be the key to cell proliferation. We find that PML–RARα acts by blocking the ATRX senescence checkpoint, resulting in its well-known immortalization phenotype. This supports the idea that disruption of the PML-associated ATRX/Daxx–H3.3 chaperone complex is a key feature of PML–RAR fusion, directly linking disruption of cellular senescence to the leukemogenic mechanism.

The PML domain of PML–RARα blocks senescence to promote leukemia