Aberrant corepressor interactions implicated in PML-RARα and PLZF-RARα leukemogenesis reflect an altered recruitment and release of specific NCoR and SMRT splice variants

Brenda J. Mengeling, Theresa Q. Phan, Michael L. Goodson, Martin L. Privalsky

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4236-4247
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number6
DOIs
StatePublished - Feb 11 2011

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Co-Repressor Proteins
Fusion reactions
Acute Promyelocytic Leukemia
Aptitude
Hormones
Retinoid X Receptors
Genetic Translocation
Retinoic Acid Receptors
Oncogene Proteins
Retinoids
Cell- and Tissue-Based Therapy
Tretinoin
Transcription Factors
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Aberrant corepressor interactions implicated in PML-RARα and PLZF-RARα leukemogenesis reflect an altered recruitment and release of specific NCoR and SMRT splice variants. / Mengeling, Brenda J.; Phan, Theresa Q.; Goodson, Michael L.; Privalsky, Martin L.

In: Journal of Biological Chemistry, Vol. 286, No. 6, 11.02.2011, p. 4236-4247.

Research output: Contribution to journalArticle

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