|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 793-802
Overexpression of Wild-Type Retinoic Acid Receptor  (RAR)
Recapitulates Retinoic Acid-Sensitive Transformation of Primary Myeloid
Progenitors by Acute Promyelocytic Leukemia RAR-Fusion Genes
Changchun Du,
Robert L. Redner,
Michael P. Cooke, and
Catherine Lavau
From Systemix Inc, Palo Alto, CA; and the University of Pittsburgh
Medical Center, Pittsburg, PA.
Retinoic acid receptor  (RAR) is the target of several
chromosomal translocations associated with acute promyelocytic
leukemias (APLs). These rearrangements fuse RAR to different partner
genes creating the chimeric proteins: PML-RAR, PLZF-RAR, and
NPM-RAR. Although the vast majority of APLs respond to retinoic acid
therapy, those associated with PLZF-RAR are resistant. We have used
retroviruses to express PML-RAR, PLZF-RAR, NPM-RAR, RAR403
(a dominant negative mutant of RAR), and wild-type RAR in murine
bone marrow progenitors and found that all of these constructs blocked
differentiation and led to the immortalization of myeloid progenitors.
This cellular transformation is specific to an alteration of the RAR
pathway because overexpression of RAR , RAR , or RXR did not
result in similar growth perturbations. Pharmacological doses of RA
induced differentiation and inhibited proliferation of cells
transformed with either of the APL fusion genes, including PLZF-RAR,
whereas physiological retinoic acid concentrations were sufficient to reverse the phenotype of cells transformed with wild-type RAR. The
cellular responses to retinoic acid were accompanied by a sharp
decrease in the amount of the RAR-fusion proteins expressed in the
cells. Our findings suggest that the oncogenicity of RAR-fusion proteins results from their nature to behave as unliganded RAR in
the presence of physiological concentrations of retinoic acid.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
E. Morgado, S. Albouhair, and C. Lavau
Flt3 is dispensable to the Hoxa9/Meis1 leukemogenic cooperation
Blood,
May 1, 2007;
109(9):
4020 - 4022.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Zhou, L. Peres, N. Honore, R. Nasr, J. Zhu, and H. de The
Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization
PNAS,
June 13, 2006;
103(24):
9238 - 9243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Heuze, F. C. Guibal, C. A. Banks, J. W. Conaway, R. C. Conaway, Y. E. Cayre, A. Benecke, and P. G. Lutz
ASB2 Is an Elongin BC-interacting Protein That Can Assemble with Cullin 5 and Rbx1 to Reconstitute an E3 Ubiquitin Ligase Complex
J. Biol. Chem.,
February 18, 2005;
280(7):
5468 - 5474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. B. Kindle, P. J. F. Troke, H. M. Collins, S. Matsuda, D. Bossi, C. Bellodi, E. Kalkhoven, P. Salomoni, P. G. Pelicci, S. Minucci, et al.
MOZ-TIF2 Inhibits Transcription by Nuclear Receptors and p53 by Impairment of CBP Function
Mol. Cell. Biol.,
February 1, 2005;
25(3):
988 - 1002.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Yen, R. Fenning, R. Chandraratna, P. Walker, and S. Varvayanis
A Retinoic Acid Receptor {beta}/{gamma}-Selective Prodrug (tazarotene) Plus a Retinoid X Receptor Ligand Induces Extracellular Signal-Regulated Kinase Activation, Retinoblastoma Hypophosphorylation, G0 Arrest, and Cell Differentiation
Mol. Pharmacol.,
December 1, 2004;
66(6):
1727 - 1737.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Ibanez, A. Sharma, S. Buonamici, A. Verma, S. Kalakonda, J. Wang, S. Kadkol, and Y. Saunthararajah
AML1-ETO Decreases ETO-2 (MTG16) Interactions with Nuclear Receptor Corepressor, an Effect That Impairs Granulocyte Differentiation
Cancer Res.,
July 1, 2004;
64(13):
4547 - 4554.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Puccetti, D. Obradovic, T. Beissert, A. Bianchini, B. Washburn, F. Chiaradonna, S. Boehrer, D. Hoelzer, O. G. Ottmann, P. G. Pelicci, et al.
AML-associated Translocation Products Block Vitamin D3-induced Differentiation by Sequestering the Vitamin D3 Receptor
Cancer Res.,
December 1, 2002;
62(23):
7050 - 7058.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Minucci, S. Monestiroli, S. Giavara, S. Ronzoni, F. Marchesi, A. Insinga, D. Diverio, P. Gasparini, M. Capillo, E. Colombo, et al.
PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors
Blood,
September 26, 2002;
100(8):
2989 - 2995.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Zhang, E. Nelson, H. S. Radomska, J. Iwasaki-Arai, K. Akashi, A. D. Friedman, and D. G. Tenen
Induction of granulocytic differentiation by 2 pathways
Blood,
May 29, 2002;
99(12):
4406 - 4412.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kawamata, C. Du, K. Li, and C. Lavau
Notch1 Perturbation of Hemopoiesis Involves Non-Cell- Autonomous Modifications
J. Immunol.,
February 15, 2002;
168(4):
1738 - 1745.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. C. Guibal, C. Moog-Lutz, P. Smolewski, Y. Di Gioia, Z. Darzynkiewicz, P. G. Lutz, and Y. E. Cayre
ASB-2 Inhibits Growth and Promotes Commitment in Myeloid Leukemia Cells
J. Biol. Chem.,
January 4, 2002;
277(1):
218 - 224.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. B. Sykes and M. P. Kamps
Estrogen-dependent E2a/Pbx1 myeloid cell lines exhibit conditional differentiation that can be arrested by other leukemic oncoproteins
Blood,
October 15, 2001;
98(8):
2308 - 2318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Kastner, H. J. Lawrence, C. Waltzinger, N. B. Ghyselinck, P. Chambon, and S. Chan
Positive and negative regulation of granulopoiesis by endogenous RAR{alpha}
Blood,
March 1, 2001;
97(5):
1314 - 1320.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Lehmann, C. Paul, and H. Törmä
Retinoid Receptor Expression and Its Correlation to Retinoid Sensitivity in Non-M3 Acute Myeloid Leukemia Blast Cells
Clin. Cancer Res.,
February 1, 2001;
7(2):
367 - 373.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
F. F. Ferrara, F. Fazi, A. Bianchini, F. Padula, V. Gelmetti, S. Minucci, M. Mancini, P. G. Pelicci, F. L. Coco, and C. Nervi
Histone Deacetylase-targeted Treatment Restores Retinoic Acid Signaling and Differentiation in Acute Myeloid Leukemia
Cancer Res.,
January 1, 2001;
61(1):
2 - 7.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
C. Lavau, R. T. Luo, C. Du, and M. J. Thirman
Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice
PNAS,
September 19, 2000;
(2000)
190167297.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
F. Grignani, M. Valtieri, M. Gabbianelli, V. Gelmetti, R. Botta, L. Luchetti, B. Masella, O. Morsilli, E. Pelosi, P. Samoggia, et al.
PML/RARalpha fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype
Blood,
August 15, 2000;
96(4):
1531 - 1537.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Du, S. Tsai, J. R. Keller, and S. C. Williams
Identification of an Interleukin-3-regulated Aldoketo Reductase Gene in Myeloid Cells Which May Function in Autocrine Regulation of Myelopoiesis
J. Biol. Chem.,
March 15, 2000;
275(10):
6724 - 6732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Kogan, S.-h. Hong, D. B. Shultz, M. L. Privalsky, and J. M. Bishop
Leukemia initiated by PMLRARalpha : the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable
Blood,
March 1, 2000;
95(5):
1541 - 1550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Lavau, R. T. Luo, C. Du, and M. J. Thirman
Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice
PNAS,
September 26, 2000;
97(20):
10984 - 10989.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
