Abstract
Acute myeloid leukemia (AML)-associated chromosomal translocations result in formation of chimeric transcription factors, such as PML/RARα, PLZF/RARα, and AML-1/ETO, of which the components are involved in regulation of transcription by chromatin modeling through histone acetylation/deacetylation. The leukemic differentiation block is attributed to deregulated transcription caused by these chimeric fusion proteins, which aberrantly recruit histone-deacetylase (HDAC) activity. One essential differentiation pathway blocked by the leukemic fusion proteins is the vitamin (Vit) D3 signaling. Here we investigated the mechanisms by which the leukemic fusion proteins interfere with VitD3-induced differentiation. The VitD3-receptor (VDR) is, like the retinoid receptors RAR, retinoid X receptor, and the thyroid hormone receptor (TR), a ligand-inducible transcription factor. In the absence of ligand, the transcriptional activity of TR and RAR is silenced by recruitment of HDAC activity through binding to corepressors. In the presence of ligand, TR and RAR activate transcription by releasing HDAC activity and by recruiting histoneacetyltransferase activity. Here we report that VDR binds corepressors in a ligand-dependent manner and that inhibition of HDAC activity increases VitD3 sensitivity of HL-60 cells. Nevertheless, the inhibition of HDAC activity is unable to overcome the block of VitD3-induced differentiation caused by PLZF/RARα expression. Here we demonstrate that the expression of the translocation products PML/RARα and PLZF/RARα impairs the localization of VDR in the nucleus by binding to VDR. Furthermore, the overexpression of VDR in U937 cells expressing AML-related translocation products completely abolishes the block of VltD3-induced differentiation. Taken together these data indicate that the AML-associated translocation products block differentiation not only by interfering with chromatin-modeling but also by sequestering factors Involved in the differentiation signaling pathways, such as VDR in the VitD3-induced differentiation.
| Original language | English |
|---|---|
| Pages (from-to) | 7050-7058 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 62 |
| Issue number | 23 |
| Publication status | Published - Dec 1 2002 |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
AML-associated translocation products block vitamin D3-induced differentiation by sequestering the vitamin D3 receptor. / Puccetti, Elena; Obradovic, Darja; Beissert, Tim; Bianchini, Andrea; Washburn, Birgit; Chiaradonna, Ferdinando; Boehrer, Simone; Hoelzer, Dieter; Ottmann, Oliver Gerhard; Pelicci, Pier Giuseppe; Nervi, Clara; Ruthardt, Martin.
In: Cancer Research, Vol. 62, No. 23, 01.12.2002, p. 7050-7058.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - AML-associated translocation products block vitamin D3-induced differentiation by sequestering the vitamin D3 receptor
AU - Puccetti, Elena
AU - Obradovic, Darja
AU - Beissert, Tim
AU - Bianchini, Andrea
AU - Washburn, Birgit
AU - Chiaradonna, Ferdinando
AU - Boehrer, Simone
AU - Hoelzer, Dieter
AU - Ottmann, Oliver Gerhard
AU - Pelicci, Pier Giuseppe
AU - Nervi, Clara
AU - Ruthardt, Martin
PY - 2002/12/1
Y1 - 2002/12/1
N2 - Acute myeloid leukemia (AML)-associated chromosomal translocations result in formation of chimeric transcription factors, such as PML/RARα, PLZF/RARα, and AML-1/ETO, of which the components are involved in regulation of transcription by chromatin modeling through histone acetylation/deacetylation. The leukemic differentiation block is attributed to deregulated transcription caused by these chimeric fusion proteins, which aberrantly recruit histone-deacetylase (HDAC) activity. One essential differentiation pathway blocked by the leukemic fusion proteins is the vitamin (Vit) D3 signaling. Here we investigated the mechanisms by which the leukemic fusion proteins interfere with VitD3-induced differentiation. The VitD3-receptor (VDR) is, like the retinoid receptors RAR, retinoid X receptor, and the thyroid hormone receptor (TR), a ligand-inducible transcription factor. In the absence of ligand, the transcriptional activity of TR and RAR is silenced by recruitment of HDAC activity through binding to corepressors. In the presence of ligand, TR and RAR activate transcription by releasing HDAC activity and by recruiting histoneacetyltransferase activity. Here we report that VDR binds corepressors in a ligand-dependent manner and that inhibition of HDAC activity increases VitD3 sensitivity of HL-60 cells. Nevertheless, the inhibition of HDAC activity is unable to overcome the block of VitD3-induced differentiation caused by PLZF/RARα expression. Here we demonstrate that the expression of the translocation products PML/RARα and PLZF/RARα impairs the localization of VDR in the nucleus by binding to VDR. Furthermore, the overexpression of VDR in U937 cells expressing AML-related translocation products completely abolishes the block of VltD3-induced differentiation. Taken together these data indicate that the AML-associated translocation products block differentiation not only by interfering with chromatin-modeling but also by sequestering factors Involved in the differentiation signaling pathways, such as VDR in the VitD3-induced differentiation.
AB - Acute myeloid leukemia (AML)-associated chromosomal translocations result in formation of chimeric transcription factors, such as PML/RARα, PLZF/RARα, and AML-1/ETO, of which the components are involved in regulation of transcription by chromatin modeling through histone acetylation/deacetylation. The leukemic differentiation block is attributed to deregulated transcription caused by these chimeric fusion proteins, which aberrantly recruit histone-deacetylase (HDAC) activity. One essential differentiation pathway blocked by the leukemic fusion proteins is the vitamin (Vit) D3 signaling. Here we investigated the mechanisms by which the leukemic fusion proteins interfere with VitD3-induced differentiation. The VitD3-receptor (VDR) is, like the retinoid receptors RAR, retinoid X receptor, and the thyroid hormone receptor (TR), a ligand-inducible transcription factor. In the absence of ligand, the transcriptional activity of TR and RAR is silenced by recruitment of HDAC activity through binding to corepressors. In the presence of ligand, TR and RAR activate transcription by releasing HDAC activity and by recruiting histoneacetyltransferase activity. Here we report that VDR binds corepressors in a ligand-dependent manner and that inhibition of HDAC activity increases VitD3 sensitivity of HL-60 cells. Nevertheless, the inhibition of HDAC activity is unable to overcome the block of VitD3-induced differentiation caused by PLZF/RARα expression. Here we demonstrate that the expression of the translocation products PML/RARα and PLZF/RARα impairs the localization of VDR in the nucleus by binding to VDR. Furthermore, the overexpression of VDR in U937 cells expressing AML-related translocation products completely abolishes the block of VltD3-induced differentiation. Taken together these data indicate that the AML-associated translocation products block differentiation not only by interfering with chromatin-modeling but also by sequestering factors Involved in the differentiation signaling pathways, such as VDR in the VitD3-induced differentiation.
UR - http://www.scopus.com/inward/record.url?scp=0036895869&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036895869&partnerID=8YFLogxK
M3 - Article
C2 - 12460926
AN - SCOPUS:0036895869
VL - 62
SP - 7050
EP - 7058
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 23
ER -