Aberrant Corepressor Interactions Implicated in PML-RAR alpha and PLZF-RAR alpha Leukemogenesis Reflect an Altered Recruitment and Release of Specific NCoR and SMRT Splice Variants

作者：Mengeling Brenda J; Phan Theresa Q; Goodson Michael L; Privalsky Martin L^*

来源：Journal of Biological Chemistry, 2011, 286(6): 4236-4247.

DOI：10.1074/jbc.M110.200964

Human acute promyelocytic leukemia is causally linked to chromosomal translocations that generate chimeric retinoic acid receptor-alpha proteins (x-RAR alpha fusions). Wild-type RAR alpha is a transcription factor that binds to the SMRT/NCoR family of corepressors in the absence of hormone but releases from corepressor and binds coactivators in response to retinoic acid. In contrast, the x-RAR alpha fusions are impaired for corepressor release and operate in acute promyelocytic leukemia as dominant-negative inhibitors of wild-type RAR alpha. We report that the two most common x-RAR alpha fusions, PML-RAR alpha and PLZF-RAR alpha, have gained the ability to recognize specific splice variants of SMRT and NCoR that are poorly recognized by RAR alpha. These differences in corepressor specificity between the normal and oncogenic receptors are further magnified in the presence of a retinoid X receptor heteromeric partner. The ability of retinoids to fully release corepressor from PML-RAR alpha differs for the different splice variants, a phenomenon relevant to the requirement for supraphysiological levels of this hormone in differentiation therapy of leukemic cells. We propose that this shift in the specificity of the x-RAR alpha fusions to a novel repertoire of corepressors contributes to the dominant-negative and oncogenic properties of these oncoproteins and helps explain previously paradoxical aspects of their behavior.

• 出版日期2011-2