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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1541-1550
PLENARY PAPER
From the G.W. Hooper Foundation and Departments of Laboratory
Medicine and Microbiology & Immunology, University of California, San
Francisco, CA; and the Section of Microbiology, Division of Biological
Sciences, University of California, Davis, CA.
The most common chromosomal translocation in acute promyelocytic
leukemia (APL), t15;17(q22;q21), creates PMLRAR
Retinoids are signaling molecules with significant
roles in development and differentiation.1,2 These biologic
effects led to the hypothesis that retinoids might be useful agents in the treatment of human malignancies. Hence, retinoids have been evaluated as possible therapies for a variety of human neoplasms including leukemias, skin cancers, cervical cancer, and
neuroblastomas.3,4 Among myeloid leukemias, acute
promyelocytic leukemia (APL) was found to be particularly sensitive to
retinoic acid5 and more than a decade has passed since the
demonstration that all-trans retinoic acid (tRA) could induce
remission in patients with APL by stimulating differentiation of the
leukemic cells.6,7 Understanding the pathogenesis and
retinoid responsiveness of APL is important for expanding the
application of retinoids in cancer treatment and for developing
additional differentiation therapies.
In 1977 Rowley and colleagues8 described a specific
association of APL with a t(15;17) chromosomal translocation.
Subsequent to the demonstration of the therapeutic benefit of tRA in
APL, the breakpoint on chromosome 17 was identified to be within a gene
encoding a retinoic acid receptor, RAR In addition to the common t(15;17) translocation, other chromosomal
translocations have been identified in rare cases of APL. These
translocations also result in fusions to RAR RAR Although almost all APL patients respond to tRA therapy, resistance to
this agent often develops in patients so treated.26,27 It
has been suggested that enhanced metabolism of tRA, increased expression of the cellular retinoic acid binding protein II, and increased expression of the multidrug resistance gene product may
contribute to clinical tRA resistance (reviewed in Ding et al28 and Imaizumi et al29). However,
alterations of the PMLRAR We previously developed a murine myeloid leukemia model that
recapitulates many of the features of APL.32 We have now
generated additional transgenic mice to assess the role of hormone
responsiveness by PMLRAR Preparation of plasmid constructs
Protease resistance assay
Transient transfections CV-1 cell transfections were performed by a lipofection method as recommended by the manufacturer (Lipofectin, Gibco-BRL). Approximately 7 × 104 cells were transfected with 25 ng of the pSG5-RAR or pSG5-PMLRAR plasmids (representing
"wild-type" or the m4 mutant), 100 ng of pCMV-lacZ (used as an
internal normalization control for the efficiency of the transfection
procedure) and 100 ng of the ptk-luciferase- RARE reporter. Five
hours after transfection, the cells were transferred into media either
lacking or containing 1 µmol tRA. Cells were harvested 48 hours after transfection and the levels of luciferase and -galactosidase were
determined.34,35
In vitro receptor/corepressor binding assays GST-fusion proteins were expressed in E coli and were purified and immobilized by binding to glutathione agarose as previously described.34 35S-methionine-labeled full-length RAR , RAR m4, PMLRAR , and
PMLRAR m4 proteins were synthesized by a coupled in vitro
transcription and translation system (Promega TnT kit, Promega,
Madison, WI). The radiolabeled proteins were subsequently incubated
with the immobilized GST fusion proteins in HEMG buffer in the presence or absence of tRA, the agarose matrix was extensively washed and bound
proteins were eluted with free glutathione and analyzed by
denaturing PAGE.33 The electrophoretograms were visualized and quantified by phosphorimager analysis (Molecular Dynamics STORM
system, Molecular Dynamics, Sunnyvale, CA).
Generation of transgenic mice The human PMLRAR m4 and RAR m4 cDNAs were cloned
into the hMRP8 expression cassette.36 Transgenic
animals were prepared following standard procedures37 from
inbred FVB/N mice.38
Western blotting and immunofluorescence Western blotting was performed as previously described with a rabbit polyclonal antiserum raised against a GST-fusion protein, encompassing amino acids 420-462 of the human RAR protein
(anti-RAR F).32,39 Whole-cell lysates of bone
marrow from control and transgenic mice were subjected to denaturing
PAGE on 8% or 12% SDS-polyacrylamide gels and were transferred to
nitrocellulose. Immunofluorescence analysis of bone marrow cells was
performed essentially as described40 but using the
anti-RAR F antiserum at a 1:150 dilution.
Isolation of cells from tissues, cell staining, and fluorescence-activated cell sorting These were performed as previously described.32,40 In addition, Sudan Black B staining was performed using reagents from Sigma, according the manufacturer's directions.Peripheral blood counts Blood was analyzed on a Hemavet veterinary hematology analyzer to assess white blood cell counts, hemoglobin, and platelet counts. White blood cell differential counts were performed on peripheral blood smears.Methylcellulose cultures Bone marrow cells were cultured in duplicate in 35 mm petri dishes in Methocult M3230 methylcellulose medium (StemCell Technologies, Vancouver, BC) supplemented with either 50 units/mL G-CSF (Boehringer Mannheim), or 2.5 ng/mL GM-CSF (StemCell Technologies) plus 2% Xg63Ag8-653-IL341 conditioned medium. One milliliter cultures contained 5 × 104 viable bone marrow cells. Analysis was as previously described.40Transplantations Cells isolated from bone marrow and spleens of leukemic animals were resuspended in buffered saline and injected into the tail veins of 6- to 12-week-old FVB/N mice, 5 × 106 viable cells/recipient. Nonleukemic bone marrow isolated from PMLRAR m4
transgenic founder #4048 was transplanted into lethally irradiated
FVB/N mice as previously described.32
Treatment with all-trans retinoic acid Leukemic mice were treated by subcutaneous implantation of 21-day release pellets containing 5 mg tRA or placebo (Innovative Research of America). Morphologic differentiation by tRA was assessed on days 4 and 11 of therapy.
Generation of transgenic mice We generated transgenic mice expressing a PMLRAR unable
to activate transcription as well as transgenic mice expressing an RAR with dominant negative activity. For this purpose, we
introduced a Leu to Pro mutation at amino acid 398 of RAR
into cDNAs encoding PMLRAR and
RAR (Figure 1A). This
mutation was originally identified by Shao and colleagues31
in a retinoic acid resistant subclone of human APL cells (NB4-R4) and
was designated the m4 mutation. The m4 mutation impairs ligand binding,
abrogates ligand-induced transcriptional activation, and blocks
ligand-induced release of SMRT corepressor.31,42
Furthermore, PMLRAR m4 and RAR m4 act as dominant
negative inhibitors of tRA-induced transcription.31
Expression of the transgenes The MRP8 promoter element can drive transgene expression in myeloid cells, including myeloblasts, neutrophils, and monocytes.32,36,40 Western blotting of bone marrow was performed using a rabbit polyclonal antiserum raised to human RAR F.32 The results are summarized in Tables
1 and 2, and
representative data are shown (Figure 2A
and B). Although the murine peptide differs from the human by only 4 of
43 amino acids, the antiserum recognizes murine RAR poorly
and as a result endogenous murine RAR is not seen on these blots. PMLRAR m4 protein was present in 5 of 7 lines of
MRP8-PMLRAR m4 transgenic mice analyzed. Levels of expression
in 2 of the lines appeared comparable to levels of PMLRAR in
our highest expressing MRP8-PMLRAR mice (Figure 2A).
RAR m4 protein was present in 5 of 7 lines of
MRP8-RAR m4 transgenic mice analyzed. Levels of expression in
2 of the lines appeared to exceed the levels of PMLRAR in
our highest expressing MRP8-PMLRAR mice (Figure 2B).
PMLRAR m4 transgenic mice (Table 1), a frequency similar
to that encountered previously in MRP8-PMLRAR transgenic
mice.32 The latency until leukemia onset, 3 to 11 months,
was also comparable to that seen in our MRP8-PMLRAR mice
(Table 1; see also Brown et al32). Assessment of leukemia
penetrance was hampered by the fact that because of early illness, poor
reproduction, or lack of transgene transmission, we did not obtain
transgenic offspring for any of the lines in which leukemias developed.
Nevertheless, it was apparent that PMLRAR m4 could readily
initiate leukemia: 3 of 7 independent founder mice developed leukemia
and 4 of 5 mice that were reconstituted with the nonleukemic bone
marrow of a fourth independent founder also developed leukemia (Table
1).
All-trans retinoic acid does not cause differentiation of
PMLRAR
RAR We and others had demonstrated that directing expression of the
PMLRAR Leukemogenesis cannot be explained by inappropriate transcriptional
activation by PMLRAR Retinoic acid responsiveness may influence leukemic phenotype
A dominant negative RAR of RAR may underlie
the pathogenesis of APL. First, retinoic acid can enhance neutrophilic differentiation.58,59 Second, dominant negative
RAR can inhibit neutrophilic maturation of primary
cells.60 Third, comparisons between PMLRAR and
PLZFRAR have focused attention on the role of these proteins
as transcriptional repressors that can interfere with normal activation
of retinoic acid responsive genes.34,42,45,56,61 Fourth,
the 4 described translocations involving RAR in APL result in fusions to PML, PLZF, NPM, and NuMA, proteins that do not appear to
share common functions. In light of the evidence that transcriptional repression is important in the pathogenesis of
APL,34,42,45,56,61 the lack of similarities between the 4 RAR partners raises the possibility that the fusion proteins
contribute to APL by acting as dominant negative RAR s. The
fact that PMLRAR and PMLRAR m4 readily initiated
leukemias, whereas RAR m4 did not, strongly suggests that the
PML domain does more than simply confer dominant negative activity onto
RAR .
Retinoic acid binding to PMLRAR m4 transgenic mice
did not differentiate in response to retinoic acid. The m4 mutation was
originally described in a subclone of the NB4 cell line selected to
grow in retinoic acid. Our results parallel the previously observed
association of the m4 mutation with resistance to differentiation, and
further demonstrate that the ability of tRA to cause differentiation of
leukemic cells requires direct effects of tRA on the PMLRAR fusion protein.
We thank Daphne Haas-Kogan and H. Jeffrey Lawrence for critical reading of the manuscript, and Meijuan Zhou for technical assistance.
Submitted June 25, 1999; accepted October 28, 1999.
Supported by grants CA 4338 and CA 75985 from the National Institutes of Health and by funds from the G.W. Hooper Research Foundation. S.C.K. is a recipient of a Burroughs Wellcome Fund Career Award.
Reprints: Scott C. Kogan, Department of Laboratory Medicine, Room M524, Box 0100, 505 Parnassus Ave, University of California, San Francisco, CA 94143-0100.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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G.-B. Zhou, J. Zhang, Z.-Y. Wang, S.-J. Chen, and Z. Chen Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy Phil Trans R Soc B, June 29, 2007; 362(1482): 959 - 971. [Abstract] [Full Text] [PDF] |
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E. L. Reineke, H. Liu, M. Lam, Y. Liu, and H.-Y. Kao Aberrant Association of Promyelocytic Leukemia Protein-Retinoic Acid Receptor-{alpha} with Coactivators Contributes to Its Ability to Regulate Gene Expression J. Biol. Chem., June 22, 2007; 282(25): 18584 - 18596. [Abstract] [Full Text] [PDF] |
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S. Yang, J.-H. Jeong, A. L. Brown, C.-H. Lee, P. P. Pandolfi, J. H. Chung, and M. K. Kim Promyelocytic Leukemia Activates Chk2 by Mediating Chk2 Autophosphorylation J. Biol. Chem., September 8, 2006; 281(36): 26645 - 26654. [Abstract] [Full Text] [PDF] |
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D. Kamashev, D. Vitoux, and H. de The PML-RARA-RXR Oligomers Mediate Retinoid and Rexinoid/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation J. Exp. Med., April 19, 2004; 199(8): 1163 - 1174. [Abstract] [Full Text] [PDF] |
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C. Gurrieri, K. Nafa, T. Merghoub, R. Bernardi, P. Capodieci, A. Biondi, S. Nimer, D. Douer, C. Cordon-Cardo, R. Gallagher, et al. Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia Blood, March 15, 2004; 103(6): 2358 - 2362. [Abstract] [Full Text] [PDF] |
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C. Gurrieri, P. Capodieci, R. Bernardi, P. P. Scaglioni, K. Nafa, L. J. Rush, D. A. Verbel, C. Cordon-Cardo, and P. P. Pandolfi Loss of the Tumor Suppressor PML in Human Cancers of Multiple Histologic Origins J Natl Cancer Inst, February 18, 2004; 96(4): 269 - 279. [Abstract] [Full Text] [PDF] |
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V. T. Phan, D. B. Shultz, B.-T. H. Truong, T. J. Blake, A. L. Brown, T. J. Gonda, M. M. Le Beau, and S. C. Kogan Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation Mol. Cell. Biol., July 1, 2003; 23(13): 4573 - 4585. [Abstract] [Full Text] [PDF] |
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B. Farboud, H. Hauksdottir, Y. Wu, and M. L. Privalsky Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors {beta} and {gamma} Interferes with Corepressor Recruitment and Prevents Transcriptional Repression Mol. Cell. Biol., April 15, 2003; 23(8): 2844 - 2858. [Abstract] [Full Text] [PDF] |
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J. Sohal, V. T. Phan, P. V. Chan, E. M. Davis, B. Patel, L. M. Kelly, T. J. Abrams, A. M. O'Farrell, D. G. Gilliland, M. M. Le Beau, et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657 Blood, April 15, 2003; 101(8): 3188 - 3197. [Abstract] [Full Text] [PDF] |
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B.-T. H. Truong, Y.-J. Lee, T. A. Lodie, D. J. Park, D. Perrotti, N. Watanabe, H. P. Koeffler, H. Nakajima, D. G. Tenen, and S. C. Kogan CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia Blood, February 1, 2003; 101(3): 1141 - 1148. [Abstract] [Full Text] [PDF] |
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J. Li, P. Chen, N. Sinogeeva, M. Gorospe, R. P. Wersto, F. J. Chrest, J. Barnes, and Y. Liu Arsenic Trioxide Promotes Histone H3 Phosphoacetylation at the Chromatin of CASPASE-10 in Acute Promyelocytic Leukemia Cells J. Biol. Chem., December 13, 2002; 277(51): 49504 - 49510. [Abstract] [Full Text] [PDF] |
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M.-C. Guillemin, E. Raffoux, D. Vitoux, S. Kogan, H. Soilihi, V. Lallemand-Breitenbach, J. Zhu, A. Janin, M.-T. Daniel, B. Gourmel, et al. In Vivo Activation of cAMP Signaling Induces Growth Arrest and Differentiation in Acute Promyelocytic Leukemia J. Exp. Med., November 18, 2002; 196(10): 1373 - 1380. [Abstract] [Full Text] [PDF] |
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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] |
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P. Westervelt, J. L. Pollock, K. M. Oldfather, M. J. Walter, M. K. Ma, A. Williams, J. F. DiPersio, and T. J. Ley Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia PNAS, July 9, 2002; 99(14): 9468 - 9473. [Abstract] [Full Text] [PDF] |
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F.-M. Boisvert, M. J. Kruhlak, A. K. Box, M. J. Hendzel, and D. P. Bazett-Jones The Transcription Coactivator Cbp Is a Dynamic Component of the Promyelocytic Leukemia Nuclear Body J. Cell Biol., March 5, 2001; 152(5): 1099 - 1106. [Abstract] [Full Text] [PDF] |
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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] |
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S. C. Kogan, D. E. Brown, D. B. Shultz, B.-T. H. Truong, V. Lallemand-Breitenbach, M.-C. Guillemin, E. Lagasse, I. L. Weissman, and J. M. Bishop Bcl-2 Cooperates with Promyelocytic Leukemia Retinoic Acid Receptor {alpha} Chimeric Protein (Pmlrar{alpha}) to Block Neutrophil Differentiation and Initiate Acute Leukemia J. Exp. Med., February 19, 2001; 193(4): 531 - 544. [Abstract] [Full Text] [PDF] |
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D. Grimwade, A. Biondi, M.-J. Mozziconacci, A. Hagemeijer, R. Berger, M. Neat, K. Howe, N. Dastugue, J. Jansen, I. Radford-Weiss, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party Blood, August 15, 2000; 96(4): 1297 - 1308. [Abstract] [Full Text] [PDF] |
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