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.
Human acute promyelocytic leukemia is causally linked to chromosomal translocations that generate chimeric retinoic acid receptor-α proteins (x-RARα fusions). Wild-type RARα 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-RARα fusions are impaired for corepressor release and operate in acute promyelocytic leukemia as dominant-negative inhibitors of wild-type RARα. We report that the two most common x-RARα fusions, PML-RARα and PLZF-RARα, have gained the ability to recognize specific splice variants of SMRT and NCoR that are poorly recognized by RARα. 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-RARα 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-RARα 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.
Department of Microbiology, College of Biological Sciences, University of California at Davis, Davis, California 95616, USA.
Brenda J
BJ
Mengeling
Theresa Q
TQ
Phan
Michael L
ML
Goodson
Martin L
ML
Privalsky
D000818:Animals; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; D012176:Retinoids; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein