Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia

Fabien Guidez, Sarah Ivins, Jun Zhu, Mats Söderström, Samuel Waxman, Arthur Z Zelent

Research output: Contribution to journalArticle

257 Citations (Scopus)

Abstract

Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARα fusion protein and responsiveness to treatment with all- trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARα fusion protein. Both PML- and PLZF-RARα possess identical RAR sequences and inhibit ATRA- induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARα protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARα, it has a very little effect on its association with the PLZF- RARα fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARα was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARα fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARα on ATRA response. Take together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARα-associated leukemias to ATRA.

Original languageEnglish (US)
Pages (from-to)2634-2642
Number of pages9
JournalBlood
Volume91
Issue number8
StatePublished - Apr 15 1998
Externally publishedYes

Fingerprint

Co-Repressor Proteins
Acute Promyelocytic Leukemia
Tretinoin
Fusion reactions
Proteins
Histone Deacetylases
Genetic Translocation
Histone Deacetylase Inhibitors
Transcription
Cell Differentiation
Leukemia
Genes
Association reactions

ASJC Scopus subject areas

  • Hematology

Cite this

Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. / Guidez, Fabien; Ivins, Sarah; Zhu, Jun; Söderström, Mats; Waxman, Samuel; Zelent, Arthur Z.

In: Blood, Vol. 91, No. 8, 15.04.1998, p. 2634-2642.

Research output: Contribution to journalArticle

Guidez, Fabien ; Ivins, Sarah ; Zhu, Jun ; Söderström, Mats ; Waxman, Samuel ; Zelent, Arthur Z. / Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. In: Blood. 1998 ; Vol. 91, No. 8. pp. 2634-2642.
@article{1e54d3a1f6f4433d9af1b65c9bf9b4b9,
title = "Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia",
abstract = "Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARα fusion protein and responsiveness to treatment with all- trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARα fusion protein. Both PML- and PLZF-RARα possess identical RAR sequences and inhibit ATRA- induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARα protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARα, it has a very little effect on its association with the PLZF- RARα fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARα was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARα fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARα on ATRA response. Take together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARα-associated leukemias to ATRA.",
author = "Fabien Guidez and Sarah Ivins and Jun Zhu and Mats S{\"o}derstr{\"o}m and Samuel Waxman and Zelent, {Arthur Z}",
year = "1998",
month = "4",
day = "15",
language = "English (US)",
volume = "91",
pages = "2634--2642",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",

}

TY - JOUR

T1 - Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia

AU - Guidez, Fabien

AU - Ivins, Sarah

AU - Zhu, Jun

AU - Söderström, Mats

AU - Waxman, Samuel

AU - Zelent, Arthur Z

PY - 1998/4/15

Y1 - 1998/4/15

N2 - Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARα fusion protein and responsiveness to treatment with all- trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARα fusion protein. Both PML- and PLZF-RARα possess identical RAR sequences and inhibit ATRA- induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARα protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARα, it has a very little effect on its association with the PLZF- RARα fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARα was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARα fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARα on ATRA response. Take together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARα-associated leukemias to ATRA.

AB - Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARα fusion protein and responsiveness to treatment with all- trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARα fusion protein. Both PML- and PLZF-RARα possess identical RAR sequences and inhibit ATRA- induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARα protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARα, it has a very little effect on its association with the PLZF- RARα fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARα was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARα fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARα on ATRA response. Take together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARα-associated leukemias to ATRA.

UR - http://www.scopus.com/inward/record.url?scp=0032522962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032522962&partnerID=8YFLogxK

M3 - Article

C2 - 9531570

AN - SCOPUS:0032522962

VL - 91

SP - 2634

EP - 2642

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -