Abstract
Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.
| Original language | English |
|---|---|
| Pages (from-to) | 3110-3115 |
| Number of pages | 6 |
| Journal | Oncogene |
| Volume | 20 |
| Issue number | 24 REV. ISS. 3 |
| DOIs | |
| Publication status | Published - May 28 2001 |
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Keywords
- Acute myeloid leukemias
- Differentiation therapy
- Histone deacetylases
- PML-RAR
ASJC Scopus subject areas
- Cancer Research
- Genetics
- Molecular Biology
Cite this
Histone deacetylases : A common molecular target for differentiation treatment of acute myeloid leukemias? / Minucci, Saverio; Nervi, Clara; Lo Coco, Francesco; Pelicci, Pier Giuseppe.
In: Oncogene, Vol. 20, No. 24 REV. ISS. 3, 28.05.2001, p. 3110-3115.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Histone deacetylases
T2 - A common molecular target for differentiation treatment of acute myeloid leukemias?
AU - Minucci, Saverio
AU - Nervi, Clara
AU - Lo Coco, Francesco
AU - Pelicci, Pier Giuseppe
PY - 2001/5/28
Y1 - 2001/5/28
N2 - Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.
AB - Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.
KW - Acute myeloid leukemias
KW - Differentiation therapy
KW - Histone deacetylases
KW - PML-RAR
UR - http://www.scopus.com/inward/record.url?scp=0035962644&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035962644&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1204336
DO - 10.1038/sj.onc.1204336
M3 - Article
C2 - 11420727
AN - SCOPUS:0035962644
VL - 20
SP - 3110
EP - 3115
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 24 REV. ISS. 3
ER -