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Departments of Histology and Medical Embryology [F. F. F., F. F., A. B., F. P., C. N.] and Cellular Biotechnology and Hematology [M. M., F. L. C.], University of Rome "La Sapienza," 00161 Rome; Institute of Internal Medicine and Oncological Sciences, 06100 Perugia [V. G.]; European Institute of Oncology, Department of Experimental Oncology, 20141 Milan [S. M., P. G. P.], Italy
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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fusion proteins PML/RAR and PLZF/RAR bind to
and constitutively repress promoters of RA target genes via aberrant
recruitment of multi-subunit complexes containing HDAC activities.
HDACs induce deacetylation of nucleosomal core histone tails, leading
to a chromatin conformation that correlates with gene silencing
(6
, 7)
. Consistent with a model in which HDACs are crucial
molecular targets of APLs, treatment with HDAC inhibitors and/or RA
reverts the blockage of differentiation of APL blasts in
vitro and induces disease remission in vivo by
inhibiting or releasing, respectively, the HDAC-RAR fusion repressor
complex (8, 9, 10, 11)
APL accounts for 
5–10% of AMLs (12)
. All other AML
subtypes express RARs but are not sensitive to RA action on
differentiation (13
, 14)
. It is not known whether such
unresponsiveness is a consequence of the leukemic state or whether it
reflects an active repression of the RA-signaling pathway. Aberrant
histone acetylation also results from chromosomal rearrangements
associated to other AML subsets. In t(8;21) AML, for example, a stable
association of AML1/ETO fusion protein with the nuclear HDAC complex is
crucial for its ability to repress transcription of AML1 target
genes and to block differentiation of hematopoietic precursors
(5
, 15 , 16)
. Considering that HDACs are part of a general
mechanism of gene silencing and that myeloid leukemogenesis is
consistently associated with translocations of genes encoding
transcription factors, we investigated whether the poor RA sensitivity
of nonpromyelocytic AMLs could reflect an active, HDAC-dependent
repression of RA transcription signaling pathway.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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The U937-AML1/ETO (U937 AE) cells were obtained by electroporation into U937 cells of an HA-tagged AML1/ETO cDNA generated and subcloned into the Zn2+-inducible mouse MT-1 promoter as described (15 , 21) . Different neomycin-selected clones were screened for AML1/ETO expression before and after Zn2+ treatment using an anti-HA antibody (BabCO). The U937 MT-MHA-AE clone 16 was selected because of its almost undetectable expression of AML1/ETO prior to Zn2+ treatment and high and persistent (up to 96 h) expression after Zn2+ treatment.
AML blasts and cell lines Kasumi-1 (AML-M2), U937 (AML-M5), and U937-AE were maintained in RPMI 1640 supplemented with 50 units/ml penicillin, 50 µg/ml streptomycin, and 10% FCS at 37°C in a humidified atmosphere containing 5% CO2. AML blasts were treated with the HDAC inhibitors TSA (WAKO Chemicals) or sodium phenylbutyrate (Sigma) for 1 h before the addition of RA (Sigma) and during the RA treatment.
Cell Proliferation and Differentiation.
Cell proliferation and differentiation were evaluated and quantified by
direct cell counting (trypan blue dye exclusion method) using a
hemocytometer chamber, light microscopy morphological examination of
Wright-Giemsa-stained cytospins, NBT dye reduction assay (at least 500
morphologically intact cells per experimental condition were counted
and corrected for viability, measured by trypan blue exclusion method),
cell cycle analysis of cells stained with propidium iodide, and direct
immunofluorescence staining of CD11b cell surface myeloid-specific
antigen (Coulter Epics XL flow cytometer; Beckman Coulter) as described
previously (21
, 22)
.
Analysis of Acetylated H3 and H4 Histones.
AML blasts were fixed in 100% methanol at room temperature for
5 min, followed by acetone for 2 min at -20°C, and incubated with
anti-acetylated histone H3 antibody (Upstate Biotechnology) according
to the manufacturer’s protocol. Immunofluorescence was detected using
a Zeiss Axioplan fluoromicroscope (Zeiss s.p.a.). Immunoblot analysis
of total cell homogenates (60 µg) was performed using an
anti-acetylated H4 antibody (Upstate Biotechnology) as described
(22)
. Immunoreactivity was determined using the ECL method
(Amersham).
Transient Cotransfection of AML Blasts and Transactivation
Assays.
AML blasts were transiently transfected with the
ßRARE3-tk-Luc, the TRE2-tk-Luc, or the
RARßpr-Luc reporter (23
, 24)
by electroporation using a
Gene-Pulser II apparatus (Bio-Rad). pcDNA3 expression vector (mock) or
pcDNA3s containing ETO, HA-AML1, or HA-AML1/ETO cDNAs (15
, 25)
were cotransfected with the above-described reporters in
U937 cells. The plasmid encoding ß-galactosidase (pSV-ßgal) was
cotransfected and used as internal control and for normalization of
reactions. Six h after electroporation, cells were treated for 16 h, lysed, and then assayed using the Luciferase Assay Kit (Promega) on
a luminometer (Berthold).
RNA Preparation and RT-PCR Analysis.
Total RNA was extracted from Ficoll-Hypaque-isolated AML patient blasts
as described (18)
. One microgram of total RNA was heated
at 65°C for 10 min and used as a template for first-strand cDNA
(cDNA) synthesis using SuperScript II RNase H Reverse Transcriptase and
random hexamers as primers (Life Technologies). cDNAs were
amplified for a total of 30 cycles at 94°C for 30 s, 57°C for
30 s, and 72°C for 45 s. Each PCR reaction contained 2 µl
of the cDNA, 0.2 mM deoxynucleotide triphosphates, 1.5
mM MgCl2, and 2.5 units of PLATINUM
Taq DNA Polymerase (Life Technologies). The RAR and AML1/ETO primers
used in the reactions have been described previously (18
, 26)
. The following oligonucleotides were used for
RARß and GAPDH transcripts: sense,
5'-AAGCT TGTCG ACGCC ACCAT GTTTG ACTGT ATGGA TG-3', and antisense,
5'-AGCCC TTACA TCCCT CACAG-3' for RARß; sense, 5'-CGGGA AGCTT GTGAT
CAATGG-3', and antisense, 5'-GGCAG TGATG GCATG GACTG-3', for GAPDH
(used as an internal control). PCR products were electrophoresed on a
1.2% agarose gel. Blots were hybridized with end-labeled 5' primers
using [32P]ATP and T4 kinase (Life
Technologies). Radioactivities were detected using a Fuji BAS1800
scanner (Raytest) and analyzed by Advanced Image Data Analyzer
(Raytest).
TGase Activity Assay.
The TGase activity assay was performed on total homogenate as described
previously (22)
by measuring the incorporation of
[3H]putrescine (12.6 Ci/mmol; Amersham Corp.)
into casein in duplicate or triplicate cultures.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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. None of the blasts expressed the APL-associated fusion proteins, as
determined by RT-PCR using specific primers for the PML, PLZF, and
RAR sequences (Refs. 18
, 20
; data not shown).
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for one representative case). Remarkably, the combined
RA + TSA treatment induced the appearance of cells with
metamyelocyte- or neutrophil-like morphology and increased the NBT
positivity up to 60–80% (Fig. 1
and Table 1
). The frequency of
apoptotic cells after 5 days of treatment with RA + TSA did
not exceed 10–20% as evaluated by fluorescence-activated cell sorting
of propidium iodide-stained cells (eight cases tested; data not shown).
Therefore, it appears that RA + TSA induced terminal myeloid
differentiation in blasts from all of the 23 AML cases tested,
independent of the presence of a specific genetic lesion. The kinetics
and extent of morphologic and functional differentiation of AML blasts
after treatment with RA + TSA were comparable with those of
five APL cases treated in parallel with RA as a single agent (not
shown).
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. Immunoblot analysis using an anti-acetylated histone H4
antibody (Fig. 2b)
showed that combined treatment with RA
and TSA or sodium phenylbutyrate (another inhibitor of HDACs already
used in clinical trials), strongly induced acetylation of histone H4.
Together, these results suggest that myeloid differentiation induced by
RA + TSA might be the consequence of a combined effect at the
level of RA target promoters: transcriptional derepression by TSA and
transcriptional activation by RA.
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2.5–3.5-fold. In the presence of 50–100 ng/ml TSA,
the magnitude of the RA response of the
ßRARE3-tk-Luc and RARßpr-Luc promoters
increased 10–20-fold and 6–9-fold, respectively (Fig. 3a)
.
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and RARß (27)
. Expression
of RAR and RARß was evaluated by
semiquantitative RT-PCR analysis performed on total RNA prepared from
AML blasts before or after treatment for 16 h with RA, TSA, or
RA + TSA. Results revealed no modification of the levels of
RAR and RARß mRNA transcripts by TSA, slight
up-regulation by RA alone, and significant up-regulation by
RA + TSA treatment (Fig. 3, b and c
,
and data not shown). Similarly, RAR and RARß mRNA transcripts were
up-regulated by RA + TSA in two AML-M2 cell lines, HL-60 and
Kasumi-1 (data not shown). We then measured cytosolic type II TGase
activity in four AML cases, two of which are shown in Fig. 3d
. Type II TGase is a gene transcriptionally
regulated by retinoids and recently shown to be a marker of RA-induced
differentiation in APL cells (8
, 22)
. Type II TGase
activity was strongly up-regulated after 3 days of treatment with
RA + TSA (Fig. 3d)
. Therefore, it appears that TSA
potentiates the RA induction of endogenous RA target genes
RAR, RARß, and type II TGase,
strongly suggesting that the promoters of RA-responsive genes are
repressed in AML blasts via mechanisms involving HDAC activities. Transcriptional activation of RA target genes by RA + TSA correlates with the correction of a crucial component of the leukemic phenotype, e.g., the differentiation block. Thus, transcriptional repression of RA target genes in AMLs might be part of the same mechanism(s) that lead to transformation. Because different genetic events, the majority of which are still unknown, underlie myeloid leukemogenesis, repression of RA target genes might be a common event in AMLs. To investigate this possibility, we evaluated the ability of TSA to confer sensitivity to RA-induced differentiation in cells expressing the AML-associated fusion protein AML1/ETO. It has been shown that AML1/ETO represses transcription of AML1 target genes and myeloid differentiation by an aberrant recruitment of a complex containing HDAC activity (5 , 15 , 16) .
We therefore evaluated the biological response to RA and TSA of the
Kasumi-1 cell line, derived from an AML-M2 patient with the t(8;21)
translocation and expressing the AML1/ETO fusion product. In this cell
line, the level of AML1/ETO expression is comparable with that
detectable in blasts from t(8;21) AML patients (see cases AML 14 and
AML 19 in Fig. 4a
). Four days of in vitro treatment with RA or TSA
as single agents induced a modest effect on the growth and
differentiation properties of Kasumi-1 cells. Combined RA + TSA treatments, instead, caused growth arrest, accumulation of cells in
the G1 phase of the cell cycle, and increased NBT
positivity and expression of differentiation marker CD11b (Table 2)
. In addition, flow-cytometric analysis of propidium iodide-stained
cells revealed only a moderate increase in the frequency of apoptosis
(5–10%) after treatment with RA + TSA (not shown).
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1.2-fold) by pharmacological doses of RA (1
µM) as single agent and strong up-regulation (15-fold) by
the combined treatment with TSA (50–100 ng/ml; Fig. 4b
). In
contrast, in the presence of similar concentrations of TSA, RA
treatment did not significantly affect the activity of the
TRE2-tk-Luc reporter gene (a synthetic reporter
containing the palindromic sequence TRE, which mediates both RA and
thyroid hormone transactivation; Refs. 27
, 28
). A
ligand-dependent assay showed that doses of TSA of 100 ng/ml also
restored ßRARE3-tk-Luc response to
physiological concentrations of RA (1–10 nM;
Fig. 4b
). The calculated EC50 values
(concentrations that give 50% efficacy) for
ßRARE3-tk-Luc transactivation potency of RA as
sole agent and RA + TSA were 240 and 9
nM, respectively. In Kasumi-1 cells, TSA greatly
increased the effects of RA treatment on acetylation of histones H3 and
H4 and type II TGase activity (data not shown and Fig. 4c
).
These findings, together with the results obtained in blasts from two
AML patients (AML patients 14 and 19) expressing the AML1/ETO fusion
(Figs. 1
2
3
4
and data not shown), strongly suggest that RA signaling is
repressed in AML1/ETO-expressing cells and that this repression can be
relieved by inhibition of HDAC activity. Thus, AML1/ETO might act as a
transcriptional repressor of the RA pathway.
To investigate this possibility more directly, we measured the effects
of AML1/ETO expression on RA response using U937-AE cells, which
express the AML1/ETO cDNA under a Zn2+-inducible
promoter, or U937 cells transiently transfected with the HA-AML1/ETO
cDNA (see Fig. 4d
for Western blotting analysis of U937-AE
or AML1/ETO-transfected U937 cells). In the absence of AML1/ETO
expression, (Fig. 4e
, U937-MT, U937-AE
-Zn, and U937 Mock), the activity of the
ßRARE3-tk-Luc promoter was induced 50-fold
by RA and potentiated by TSA by a factor of 10. Strikingly, the
induction of AML1/ETO expression in these cells led to a marked
reduction (75%) of the RA-induced transactivation of the
ßRARE3-tk-Luc. Notably, TSA treatment relieved
transcriptional repression by AML1/ETO (Fig. 4e)
. Thus, it
appears that in myeloid cells the ß-RARE element, which is present in
promoters of RA target genes, including myeloid genes (1)
,
is activated by the combined RA + TSA treatment and is
repressed by AML1/ETO expression.
To evaluate the specificity of the effect of AML1/ETO on the
RA-signaling pathway, we next analyzed the effects of AML1, ETO, and
AML1/ETO on RA-dependent transactivation. To this end, we performed
cotransfection experiments in U937 cells using the expression vectors
for ETO, AML1B, or AML1/ETO and the
ßRARE3-tk-Luc promoter. Relative AML1, ETO, and
AML1/ETO expression levels in U937-AE and U937 transfected cells were
measured by immunoblotting analysis using an anti-HA (recognizing
HA-AML1 and HA-AML1/ETO) or an anti-ETO (recognizing overexpressed ETO,
but not the AML1/ETO fusion)
antibody,5
as shown in Fig. 4d
(for a representative experiment).
Results showed that (a) overexpression of ETO or AML1 did
not repress RA- or RA + TSA-induced
ßRARE3-tk-Luc activity (Fig. 4e
; a
slight increase in ßRARE3-tk-Luc activity was
seen after ETO expression), and (b) induction of AML1/ETO
expression by Zn2+ treatment (in the U937-AE
clone) or by transient transfection (into the parental U937 cells)
strongly repressed RA-induced ßRARE3-tk-Luc
activity (Fig. 4e)
. Taken together, these results suggest
that AML1/ETO (but not AML1 or ETO), when expressed in myeloid cells,
acts as a specific transcriptional repressor of the RA pathway.
Indirect evidence suggest that common mechanisms underlie myeloid
leukemogenesis: (a) The genes involved in the AML-associated
translocations invariably encode transcription factors
(e.g., AML1, CBFß, RAR, MLL, p300, CBP, HOX genes, and
EVI1), which are physiologically involved in hematopoietic
differentiation and cooperatively regulate promoters or enhancers
present on myeloid specific genes (1
, 5
, 12)
.
(b) Accumulation of undifferentiated precursors is a
prominent feature of the myeloid leukemia phenotype, and ectopic
expression of fusion proteins in hemopoietic precursors induces
blockage of differentiation and leukemia in animal models (10
, 29, 30, 31, 32)
. (c) Aberrant recruitment of HDAC complexes
is crucial to the activity of the AML-specific fusion proteins
PML/RAR, PLZF/RAR, and AML1/ETO (8, 9, 10
, 15
, 16)
,
suggesting that modification of the chromatin structure in the target
promoters of fusion proteins represents an important mechanism of
leukemogenesis. Thus, it is conceivable that different genetic
alterations may result in common patterns of deregulated gene
expression, leading to blockage of differentiation and favoring myeloid
leukemogenesis. Here we show that in AMLs, regardless of their
underlying genetic alteration, the RA-signaling pathway is
constitutively repressed through an HDAC-dependent mechanism and that
inhibition of HDAC activities restores the RA-differentiation response.
These results indicate that repression of the RA-signaling pathway is a
general pathogenetic event in AMLs and that HDACs are common targets
for AMLs, highlighting the possibility of
transcriptional/differentiation therapy in AMLs other than APL.
Butyrate has been used as single agent in the treatment of an AML patient resistant to conventional chemotherapy, and was shown to trigger terminal differentiation of leukemic blasts in vivo (33) . The usage of butyrates and their derivatives as HDAC inhibitors, however, is limited by their poor specificity, as well as by their transient and reversible activities. Indeed, high drug plasma concentrations must be sustained to obtain a biological effect (11) . In contrast, TSA is a highly specific, stable, and potent HDAC inhibitor. We recently demonstrated that "in vivo " modulation of gene transcription by micromolar concentrations of TSA is not toxic in adult mice and does not perturb mouse embryonic or postnatal development,6 thereby suggesting that TSA might represent a useful agent for transcriptional/differentiation therapy in AMLs.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 F. F. and A. B. were supported by fellowships
from Associazione Italiana Ricerca sul Cancro (AIRC) and Federazione
Italiana Ricerca Cancro (FIRC), respectively. This work was supported
by AIRC, Associazione Italiana Contro Le Leucemie-Linfomi, AIL,
Ministero dell’Università e Ricerca Scientifica e Tecnologica,
and Ministero della Sanità. 
2 The authors contributed equally to the work.
3 To whom requests for reprints should be
addressed, at Department of Histology and Medical Embryology,
University of Rome "La Sapienza," 00161 Rome, Italy. E-mail: clara.nervi{at}uniroma1.it
4 The abbreviations used are: RA, retinoic acid;
APL, acute promyelocytic leukemia; RAR, retinoic acid receptor ;
HDAC, histone deacetylase; AML, acute myeloid leukemia; RT-PCR, reverse
transcription-PCR; NBT, nitroblue tetrazolium; GAPDH,
glyceraldehyde-3-phosphate dehydrogenase; TGase, transglutaminase.
5 V. Gelmetti and P. G. Pelicci, unpublished
results.
6 C. Nervi, V. Buffa, F. Fazi, U. Borello, P. G.
Pelicci, and C. Gossu, submitted for publication.
Received 8/28/00. Accepted 11/13/00.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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1 and 
. Blood, 92: 607-615, 1998. (RAR) recapitulates retinoic acid-sensitive transformation of primary myeloid progenitors by acute promyelocytic leukemia RAR-fusion genes. Blood, 94: 793-802, 1999. recruit histone deacetylase in promyelocytic leukaemia. Nature (Lond.), 391: 815-818, 1998.[Medline]
and PLZF-RAR with corepressors determine differential responses to RA in APL. Nat. Genet., 18: 126-135, 1998.[Medline]
-positive acute promyelocytic leukemia by combined all-trans-retinoic acid and idarubicin (AIDA) therapy. Blood, 90: 1014-1021, 1997. fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell, 74: 423-429, 1993.[Medline]
-mediated increase of type II transglutaminase. Blood, 87: 1939-1950, 1996. under control of cathepsin G regulatory sequences. Blood, 89: 376-387, 1997. transgenic mice. Proc. Natl. Acad. Sci. USA, 94: 5302-5307, 1997. impairs myelopoiesis. Proc. Natl. Acad. Sci. USA, 93: 7900-7904, 1996. transgene initiates murine acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA, 945: 2551-2556, 1997.
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J. C. Byrd, G. Marcucci, M. R. Parthun, J. J. Xiao, R. B. Klisovic, M. Moran, T. S. Lin, S. Liu, A. R. Sklenar, M. E. Davis, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia Blood, February 1, 2005; 105(3): 959 - 967. [Abstract] [Full Text] [PDF]
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A. Glasow, N. Prodromou, K. Xu, M. von Lindern, and A. Zelent Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways Blood, January 1, 2005; 105(1): 341 - 349. [Abstract] [Full Text] [PDF]
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M. Witcher, H. Y. Shiu, Q. Guo, and W. H. Miller Jr Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells Blood, November 15, 2004; 104(10): 3335 - 3342. [Abstract] [Full Text] [PDF]
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M. Shimizu, M. Suzui, A. Deguchi, J. T. E. Lim, D. Xiao, J. H. Hayes, K. P. Papadopoulos, and I. B. Weinstein Synergistic Effects of Acyclic Retinoid and OSI-461 on Growth Inhibition and Gene Expression in Human Hepatoma Cells Clin. Cancer Res., October 1, 2004; 10(19): 6710 - 6721. [Abstract] [Full Text] [PDF]
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A. Kuendgen, C. Strupp, M. Aivado, A. Bernhardt, B. Hildebrandt, R. Haas, U. Germing, and N. Gattermann Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid Blood, September 1, 2004; 104(5): 1266 - 1269. [Abstract] [Full Text] [PDF]
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 C. Muller-Tidow, B. Steffen, T. Cauvet, L. Tickenbrock, P. Ji, S. Diederichs, B. Sargin, G. Kohler, M. Stelljes, E. Puccetti, et al. Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells Mol. Cell. Biol., April 1, 2004; 24(7): 2890 - 2904. [Abstract] [Full Text] [PDF]
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P. Atadja, L. Gao, P. Kwon, N. Trogani, H. Walker, M. Hsu, L. Yeleswarapu, N. Chandramouli, L. Perez, R. Versace, et al. Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824 Cancer Res., January 15, 2004; 64(2): 689 - 695. [Abstract] [Full Text] [PDF]
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A. Gozzini, E. Rovida, P. Dello Sbarba, S. Galimbert, and V. Santini Butyrates, as a Single Drug, Induce Histone Acetylation and Granulocytic Maturation: Possible Selectivity on Core Binding Factor-Acute Myeloid Leukemia Blasts Cancer Res., December 15, 2003; 63(24): 8955 - 8961. [Abstract] [Full Text] [PDF]
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 L. Kopelovich, J. A. Crowell, and J. R. Fay The Epigenome as a Target for Cancer Chemoprevention J Natl Cancer Inst, December 3, 2003; 95(23): 1747 - 1757. [Abstract] [Full Text] [PDF]
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 Y. Lu, I. Goldenberg, L. Bei, J. Andrejic, and E. A. Eklund HoxA10 Represses Gene Transcription in Undifferentiated Myeloid Cells by Interaction with Histone Deacetylase 2 J. Biol. Chem., November 28, 2003; 278(48): 47792 - 47802. [Abstract] [Full Text] [PDF]
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 K. K. Mann, A. Rephaeli, A. L. Colosimo, Z. Diaz, A. Nudelman, I. Levovich, Y. Jing, S. Waxman, and W. H. Miller Jr. A Retinoid/Butyric Acid Prodrug Overcomes Retinoic Acid Resistance in Leukemias by Induction of Apoptosis Mol. Cancer Res., October 1, 2003; 1(12): 903 - 912. [Abstract] [Full Text] [PDF]
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 W. Shi, A. Hoeflich, H. Flaswinkel, M. Stojkovic, E. Wolf, and V. Zakhartchenko Induction of a Senescent-Like Phenotype Does Not Confer the Ability of Bovine Immortal Cells to Support the Development of Nuclear Transfer Embryos Biol Reprod, July 1, 2003; 69(1): 301 - 309. [Abstract] [Full Text] [PDF]
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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]
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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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C. Pisano, P. Kollar, M. Gianni, Y. Kalac, V. Giordano, F. F. Ferrara, R. Tancredi, A. Devoto, A. Rinaldi, A. Rambaldi, et al. Bis-indols: a novel class of molecules enhancing the cytodifferentiating properties of retinoids in myeloid leukemia cells Blood, November 15, 2002; 100(10): 3719 - 3730. [Abstract] [Full Text] [PDF]
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J. Jaboin, J. Wild, H. Hamidi, C. Khanna, C. J. Kim, R. Robey, S. E. Bates, and C. J. Thiele MS-27-275, an Inhibitor of Histone Deacetylase, Has Marked in Vitro and in Vivo Antitumor Activity against Pediatric Solid Tumors Cancer Res., November 1, 2002; 62(21): 6108 - 6115. [Abstract] [Full Text] [PDF]
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 K. A. Strait, B. Dabbas, E. H. Hammond, C. T. Warnick, S. J. Ilstrup, and C. D. Ford Cell Cycle Blockade and Differentiation of Ovarian Cancer Cells by the Histone Deacetylase Inhibitor Trichostatin A Are Associated with Changes in p21, Rb, and Id Proteins Mol. Cancer Ther., November 1, 2002; 1(13): 1181 - 1190. [Abstract] [Full Text] [PDF]
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S. Cote, A. Rosenauer, A. Bianchini, K. Seiter, J. Vandewiele, C. Nervi, and W. H. Miller Jr Response to histone deacetylase inhibition of novel PML/RARalpha mutants detected in retinoic acid-resistant APL cells Blood, September 18, 2002; 100(7): 2586 - 2596. [Abstract] [Full Text] [PDF]
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M. C. Petti, F. Fazi, M. Gentile, D. Diverio, P. De Fabritiis, M. S. De Propris, R. Fiorini, M. A. A. Spiriti, F. Padula, P. G. Pelicci, et al. Complete remission through blast cell differentiation in PLZF/RARalpha -positive acute promyelocytic leukemia: in vitro and in vivo studies Blood, July 18, 2002; 100(3): 1065 - 1067. [Abstract] [Full Text] [PDF]
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 A. D. Weston, R. A.S. Chandraratna, J. Torchia, and T. M. Underhill Requirement for RAR-mediated gene repression in skeletal progenitor differentiation J. Cell Biol., July 8, 2002; 158(1): 39 - 51. [Abstract] [Full Text] [PDF]
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 B. M. Scicchitano, L. Spath, A. Musaro, M. Molinaro, S. Adamo, and C. Nervi AVP Induces Myogenesis through the Transcriptional Activation of the Myocyte Enhancer Factor 2 Mol. Endocrinol., June 1, 2002; 16(6): 1407 - 1416. [Abstract] [Full Text] [PDF]
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M. B. Sporn Hobson's Choice and the Need for Combinations of New Agents for the Prevention and Treatment of Breast Cancer J Natl Cancer Inst, February 20, 2002; 94(4): 242 - 243. [Full Text] [PDF]
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V. Vivat-Hannah, D. You, C. Rizzo, J.-P. Daris, P. Lapointe, F. C. Zusi, A. Marinier, M. V. Lorenzi, and M. M. Gottardis Synergistic Cytotoxicity Exhibited by Combination Treatment of Selective Retinoid Ligands with Taxol (Paclitaxel) Cancer Res., December 1, 2001; 61(24): 8703 - 8711. [Abstract] [Full Text] [PDF]
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J. Zhu, C. M. Heyworth, A. Glasow, Q.-H. Huang, K. Petrie, M. Lanotte, G. Benoit, R. Gallagher, S. Waxman, T. Enver, et al. Lineage restriction of the RAR{alpha} gene expression in myeloid differentiation Blood, October 15, 2001; 98(8): 2563 - 2567. [Abstract] [Full Text] [PDF]
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J. M. Amann, J. Nip, D. K. Strom, B. Lutterbach, H. Harada, N. Lenny, J. R. Downing, S. Meyers, and S. W. Hiebert ETO, a Target of t(8;21) in Acute Leukemia, Makes Distinct Contacts with Multiple Histone Deacetylases and Binds mSin3A through Its Oligomerization Domain Mol. Cell. Biol., October 1, 2001; 21(19): 6470 - 6483. [Abstract] [Full Text] [PDF]
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M. A. Smith and B. Anderson Where to Next with Retinoids for Cancer Therapy? Clin. Cancer Res., October 1, 2001; 7(10): 2955 - 2957. [Full Text] [PDF]
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 K. S. J. Elenitoba-Johnson Complex Regulation of Telomerase Activity : Implications for Cancer Therapy Am. J. Pathol., August 1, 2001; 159(2): 405 - 410. [Full Text]
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C. Nervi, U. Borello, F. Fazi, V. Buffa, P. G. Pelicci, and G. Cossu Inhibition of Histone Deacetylase Activity by Trichostatin A Modulates Gene Expression during Mouse Embryogenesis without Apparent Toxicity Cancer Res., February 1, 2001; 61(4): 1247 - 1249. [Abstract] [Full Text]
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