Here's the abstract from Nature Genetics:
Volume 18 Number 2 - February 1998
articles
Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors
determine differential responses to RA in APL
Li-Zhen He1, Fabien Guidez2, Carla Tribioli1, Daniela Peruzzi1, Martin Ruthardt3, Arthur Zelent2 &
Pier Paolo Pandolfi1
1Department of Human Genetics, Memorial Sloan-Kettering Cancer Center and Molecular Biology
Program, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA.
2Leukaemia Research Fund Center at the Institute for Cancer Research, Chester Beatty
Laboratories, 2307 Fulham Road, London SW3 6JB, UK. 3Istituto Oncologico Europeo, Milano,
Italy and Department of Haematology, Med. Klinik III, J.W. Goethe-University, 7 Theodor Stern
Kai, 60590 Frankfurt/Main, Germany. Correspondence should be addressed to P.P.P. e-mail:
p-pandolfi@ski.mskcc.org
Acute promyelocytic leukaemia (APL), associated with chromosomal translocations
involving the retinoic acid receptor alpha gene (RARA) and the PML gene, is sensitive
to retinoic acid (RA) treatment, while APL patients harbouring translocations between
RARA and the PLZF gene do not respond to RA. We have generated PML-RARA
and PLZF-RARA transgenic mice and show here that these fusion proteins play a
critical role in leukaemogenesis and in determining responses to RA in APL, because
PLZF-RARA transgenic mice develop RA-resistant leukaemia, while PML-RARA
mice are responsive to RA treatment. We demonstrate that both PML-RARalpha and
PLZF-RARalpha fusion proteins can act as transcriptional repressors and are able to
interact with nuclear receptor transcriptional co-repressors, such as SMRT.
PLZF-RARalpha , but not PML-RARalpha , can form, via its PLZF moiety,
co-repressor complexes which are insensitive to RA. Histone deacetylase inhibitors
such as Trichostatin A (TSA), in combination with RA, can overcome the
transcriptional repressor activity of PML-RARalpha and PLZF-RARalpha as well as
the unresponsiveness of PLZF-RARalpha -expressing leukaemic cells to RA. Thus,
our findings unravel a crucial role for transcriptional silencing in APL pathogenesis and
resistance to RA in APL. |
