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REVIEW ARTICLE
Chromatin Remodeling and Leukemia: New Therapeutic Paradigms
By Robert L. Redner, Jianxiang Wang, and Johnson M. Liu
L
OCAL REMODELING OF chromatin is a key step in the
transcriptional activation of genes. Dynamic changes in
the nucleosomal packaging of DNA must occur to allow
transcriptional proteins contact with the DNA template. The
realization that the proteins that regulate the modification of
chromatin are themselves disrupted in many leukemic chromosomal rearrangements has generated new excitement in the
study of chromatin structure. Recent reports have kindled the
hope that pharmacological manipulation of chromatin remodeling might develop into a potent and specific strategy for the
treatment of these leukemias. In this review, we will discuss the
structure of chromatin and the mechanisms by which cells
remodel chromatin, alteration of these pathways in leukemias,
and therapeutic approaches.
CHROMATIN: BEADS ON A STRING OR STRING
ON BEADS?
The condensation of DNA into an ordered chromatin structure allows the cell to solve the topological problems associated
with storing huge molecules of chromosomal DNA within the
nucleus. DNA is packaged into chromatin in orderly repeating
protein-DNA complexes called nucleosomes.1,2 Each nucleosome consists of approximately 146 bp of double-stranded
DNA wrapped 1.8 times around a core of 8 histone molecules
(Fig 1). Two molecules each of H2A, H2B, H3, and H4
comprise the histone ramp around which the DNA superhelix
winds. Stretches of DNA up to 100 bp separate adjacent
nucleosomes. Multiple nuclear proteins bind to this linker
region, some of which may be responsible for the ordered
wrapping of strings of nucleosomes into higher-order chromatin
structures.3,4
Nucleosomal structure has been well characterized by x-ray
crystallographic studies, most recently to a resolution of 2.8 Å.1
The histones are arranged as heterodimers of H2A and H2B, H3
and H4; the heterodimers, in turn, form a tetrameric structure
known as the octamer core. Each histone heterodimer binds
approximately 30 bp of DNA through electrostatic contacts with
the phosphate backbone in the minor groove of the DNA. The
interaction with histones causes the DNA to become distorted
and bend and bulge at several positions: this twisting of the
helix results in a deviation of the periodicity of the basepairs as
they spiral along the DNA superhelix. The change in periodicity
leads to alignment of the DNA minor grooves to form channels,
through which pass the random-coil histone tails. The histone
tails are thus able to contact the DNA on the exterior of the
nucleosomal particle to further stabilize DNA/histone interactions.
Although nucleosomal architecture depends primarily on
nonspecific interactions between histones and the phosphate
backbone of DNA, the thermodynamic stability of the interaction is influenced by the basepair composition of the DNA.
A-T–rich sequences in particular impart the DNA with flexibility that allows it to form the tertiary structures necessary for
optimal nucleosomal packing.1,5 In addition, histone leucine
residues bound to the minor groove of DNA are able to interact
Blood, Vol 94, No 2 (July 15), 1999: pp 417-428
with nearby thymidine residues; arginines form hydrogen bonds
with neighboring pyrimidines. These sequence-specific characteristics likely contribute to variations in the number of bases in
each nucleosome particle, the length of internucleosomal spacer
DNA, and the phasing of adjacent nucleosomes.
NUCLEOSOMAL REMODELING
Both distortion of the periodicity of the superhelix and
electrostatic shielding by the positively charged histones act to
constrain the access of nonhistone proteins to nucleosomal
DNA.6,7 Extensive remodeling of chromatin structure, particularly at cis-acting promoter sites necessary for transcriptional
initiation, must take place for the DNA template to become
accessible to the transcriptional machinery. A complete picture
of the way in which DNA separates from nucleosomes during
transcription is not yet available, but most likely only partial
dissociation from the core histones is necessary.8
Several mechanisms have been identified that contribute to
chromatin remodeling. They vary from those that alter histoneDNA interaction to those that physically dissociate the DNA
from histones in an ATP-dependent manner to those that
destabilize histone-histone tetramerization (see the recent review by Tsukiyama and Wu9 for a more detailed discussion). All
of these processes likely act simultaneously and in concert to
regulate access to the DNA template. Two of the mechanisms
are particularly relevant to the discussion of leukemic fusion
proteins (see below): histone acetylation and ATPase-mediated
DNA-histone dissociation.
The best understood mechanism by which cells regulate
chromatin structure is posttranslational modification of histones
by acetylation.10-15 Change in electrostatic attraction for DNA
and steric hindrance introduced by the hydrophobic acetyl
group leads to destabilization of the interaction of histones with
DNA.1,11-13,15,16 Lysine residues in the N-terminal extensions of
H2B, H3, and H4 that bind to the exterior surface of nucleosomes are particularly accessible to acetylation. Acetylation of
residues within the octamer core interferes with formation of
the histone heterodimers and tetramers around which the DNA
winds. Furthermore, posttranslational modification of histones
interferes with interactions with nonhistone, chromatinassociated proteins, such as MeCP2 (which binds to methylated
regions of DNA17) and the high-mobility group proteins
From the Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; and the
Hematology Branch, National Heart, Lung and Blood Institute, Bethesda
MD.
Submitted February 4, 1999; accepted April 19, 1999.
Supported by National Institutes of Health Grant No. CA67346 and
American Institute for Cancer Research Grant No. 98B039 to R.L.R.
Address reprint requests to Robert L. Redner, MD, E1058 Biomedical
Science Tower, University of Pittsburgh Medical Center, 211 Lothrop St,
Pittsburgh, PA 15213; e-mail: redner⫹@pitt.edu.
r 1999 by The American Society of Hematology.
0006-4971/99/9402-0049$3.00/0
417
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418
REDNER, WANG, AND LIU
(HMG,18,19 so named for their properties in electrophoretic
fields), which also contribute to higher-order nucleosomal
packing. In summary, acetylation of histones disrupts nucleosomes and allows the DNA to become accessible to transcriptional machinery. Removal of the acetyl groups allows the
histones to bind more tightly to DNA and to maintain a
transcriptionally repressed chromatin architecture. Acetylation
is mediated by a series of enzymes with histone acetylase
(histone acetyl transferase [HAT]) activity; conversely, acetyl
groups are removed by specific histone deacetylase (HDAC)
enzymes.
The ability to modulate histone acetylation in a gene-specific
fashion presents a challenge for cells. The state of histone
acetylation is determined by the balance between competing
enzymatic activities of histone acetyltransferases and deacetylases. Fine regulation of the catalytic activities of these enzymes
likely involves cooperative subunit interaction and posttranslational modification. However, our limited understanding of the
regulation of gene-specific histone acetylation is best captured
in the rather simplistic model of local recruitment of acetylases
or deacetylases by sequence-specific DNA binding proteins.
The paradigm for local remodeling of chromatin through
gene-specific recruitment of HAT activity is the retinoic acid
receptor (RAR).20 Because RAR-mediated chromatin remodeling is perturbed in acute promyelocytic leukemia (APL; see
below), it is appropriate to consider this model in some depth;
similar models have been developed for other transcriptional
activators and repressors.21 RAR is a ligand-dependent transcriptional activator.22 Through its zinc (Zn) finger domain, it binds
as a heterodimer with a related protein, RXR,23 to a well-defined
consensus DNA sequence found in the promoters of retinoic
acid-responsive genes.24 In the absence of ligand (retinoic acid
[RA]), the RXR/RAR heterodimer binds to DNA and actively
represses transcription below the basal level expected from
random initiation by the transcriptional machinery.25a It does
this through an indirect mechanism. The RXR/RAR heterodimer binds a nuclear corepressor molecule, either NCoR26,27 (Nuclear Receptor Co-Repressor) or SMRT28,29 (Silencing Mediator of Retinoid and Thyroid Receptors), through
specific interaction domains in the ligand-binding region of
RAR. N-CoR, the better analyzed of the 2, binds to many
sequence-specific DNA-binding transcriptional repressor proteins (Table 1). N-CoR (or SMRT) itself binds another intermediary protein, Sin3, which serves as a bridge to HDAC1, a
histone deacetylase30-32 (there have been 3 homologous HDACs
Table 1. Corepressor Proteins
Homolog
N-CoR (Nuclear
Receptor Corepressor)
SMRT (Silencing
Mediator of Retinoid and Thyroid
Receptors)
Sin3
SMRT
Nuclear receptors,
others
No
N-CoR
Nuclear receptors,
others
No
N-CoR or SMRT DNAbinding proteins
Sin3
No
HDAC
Binds to
Deacetylase
Activity
Protein
Yes
Table 2. Histone Acetylases
Human Histone
Acetylase
Alternate Name
p300
PCAF (CBP-associated factor)
NCoA-1 (nuclear
coactivator-1)
NCoA-2
p/CIP (p300/CBP
cointegratorassociated protein)
TAFII250
MOZ
Homolog
CBP (CREBbinding protein)
Part of
Coactivator
Complex
Yes
Yes
SRC-1
NCoA-2, p/CIP
Yes
TIF-2, GRIP-1
RAC3/AIBI/ACTR
NCoA-1, p/CIP
NCoA-1, NCoA-2
Yes
Yes
No
No
identified in human cells33). Thus, the end result of the
association of unliganded RAR/RXR with N-CoR is to recruit
HDAC1 to the local environment of the promoter. By removing
acetyl groups from histones and restructuring the chromatin into
a repressive configuration, HDAC1 serves as the effector
molecule in this pathway. N-CoR, Sin3, and HDAC1 function
in many repressive pathways, including transcriptional silencing by the MAD/MAX members of the MYC family,30,31,34,35
ETO36-38 (see below), and other members of the steroid
hormone receptor superfamily.26,32
Binding of ligand to RAR initiates a conformational change
in the C-terminus of RAR, which contains the N-CoR binding
site.39-41 An amphipathic helix within RAR (helix 12, which is
highly conserved within the steroid receptor superfamily)
swings into a position that both locks the ligand into its binding
pocket and creates a new hydrophobic domain. N-CoR does not
bind to this altered conformation of RAR, and hence the
N-CoR/Sin3/HDAC1 complex dissociates itself from liganded
RAR. In its place, the newly created hydrophobic domain
within RAR binds a large multimolecular complex that enhances transcriptional activation.21,42,43 Several components of
this coactivator complex have been identified (Table 2), including the adenovirus E1A-associated protein p300, pCAF (CBPassociated factor44), and a family of homologous 160-kD
proteins, including p/CIP (p300/CBP cointegrator-associated
protein),43,45 NCoA-146 (nuclear coactivator-1, also known as
SRC-142), and NCoA-2 (also known as TIF-246-48). p300, or the
homologous cyclic-AMP response-element-binding protein cofactor CBP,21,43,49,50 has been shown to interact through nonoverlapping domains with at least a dozen DNA-binding transcriptional activators, including other members of the steroid
hormone receptor family, members of the STAT family, Jun,
Fos, AML1, and Myb (see review by Giles et al51). In this
regard, p300/CBP serves as a bridge between multiple transcriptional activators. Several members of this complex have HAT
activity, including pCAF,44,52 the 160-kD proteins,53 and p300/
CBP itself.50 Thus, recruitment of the coactivator complex
brings several histone acetylases to the proximity of the
promoter to which RAR binds, so that the deacetylated histones
can be efficiently acetylated. The coactivator complex serves to
reverse the suppressive effects of the N-CoR/Sin3/HDAC1
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CHROMATIN REMODELING IN LEUKEMIA
complex and, by decreasing the affinity of histones for DNA,
remodel nucleosomal configuration so that the DNA template
can be accessed for transcription. It is as yet unclear which of
the proteins in the complex directly interact with histones,
which acetylate other proteins in the complex (or the proteins
that comprise the basal transcriptional machinery), which
stabilize the nascent basal transcriptional machinery or, which,
as has been proposed for p300/CBP, function in all 3 capacities.50
An interesting twist to this paradigm has recently arisen
through studies of DNA methylation, which has been a longaccepted mechanism of transcriptional suppression54,55. A possible contributor to the transcriptional-silencing effect of DNAmethylation may be the MeCP family of proteins, which
specifically bind to regions of methylated DNA between
adjacent nucleosomes.56 The MeCP2 protein directly binds
Sin3/HDAC1.17 Thus, by recruiting a histone deacetylase,
MeCP2-binding leads to a change in the state of histone
acetylation and in the chromatin structure of methylated DNA.
Whether this mechanism directly mediates the transcriptional
silencing effects of DNA methylation or whether it serves a
synergistic or supporting role is not yet clear. However, it leads
to the interesting speculation that DNA-methyltransferase inhibitors such as 5-azacytidine57 might alter transcriptional activity
by indirectly remodeling regions of methylated chromatin.
A second mechanism for alteration of chromatin that is less
well understood than acetylation of histones involves an
ATP-dependent enzymatic activity that directly acts on nucleosomal structure. Based on analogous protein complexes in yeast
and Drosophila (known by the acronyms SWI/SNF,58-62 NURF,63
and RSC64,65), it has been proposed that these complexes act as
ATP-dependent motors that track along the DNA strands and
pull them away from the histone octamer cores.59-62,66 During
this shift of histone-DNA contact points, the DNA would
presumably become accessible to the transcriptional machinery.
However, there is conflicting evidence to suggest that these
complexes serve to maintain chromatin in a repressive configuration, perhaps through dissociating other chromatin-associated
proteins from the DNA, such as errant TATA-binding protein.67
Reinforcing the concept of interplay between the chromatin
remodeling mechanisms is the finding that 2 members of the
human p300-associated coactivator complex68,69 have the predicted ATPase activities requisite for a SWI/SNF type of engine.
DISRUPTION OF CHROMATIN REMODELING
MECHANISMS IN LEUKEMIA
APL: Abnormal histone deacetylation. Chromatin remodeling is fundamental to transcription. The models presented above
outline the normal control of chromatin remodeling during
gene-specific transcription. Disruption of these mechanisms
gives rise to transcriptional chaos and leukemic transformation.
The best understood example of this is in APL (FrenchAmerican-British [FAB] M3).
APL holds a unique position in the study of leukemias in that
it is the only form of leukemia and the only malignancy
described to date that responds to differentiation therapy. First
published in Blood by Huang et al70 from the Shanghai Institute
of Hematology, APL blasts undergo terminal differentiation in
response to all-trans retinoic acid (ATRA). Differentiation
419
therapy with ATRA has become the mainstay of therapy for this
disease.71,72 Although relapses uniformly occur when used by
itself, in combination with conventional chemotherapy, ATRA
has revolutionized the treatment of APL, generating response
rates of close to 90%, with 3-year disease-free survival greater
than 75%.73
The explanation for the restriction of the success of ATRA
therapy to the M3 subtype of leukemias likely lies in the
chromatin alterations induced by the RAR-fusion proteins
expressed uniquely in APL cells (Fig 2). RAR␣ (there are 3
homologous RAR proteins, called ␣, ␤, and ␥) is a transcriptional activator that binds to specific DNA sequences and
inducibly recruits corepressor or coactivator complexes to
regulate transcription of retinoic acid-responsive genes (see
above). Ordered expression of retinoic acid-responsive genes is
necessary for myeloid development; dominant-negative mutants of RAR␣ inhibit myeloid maturation at the promyelocytic
stage.74,75 All patients with APL have a chromosomal translocation within the second intron of the RAR␣ locus on chromosome
17q12 to produce a chimeric protein comprised of all but the
first 30 AA of RAR␣.76 The N-terminal fusion partners are
PML77,78 on chromosome 15q21, PLZF79 on chromosome
11q23, NPM80 on chromosome 5q31, or NUMA81 on chromosome 11q13. The PML-fusion is the most common: only 8
patients with PLZF-RAR␣,82 3 with NPM-RAR␣,80 and 1 with
NUMA-RAR␣81 have been described to date. All of these
RAR␣ fusion proteins contain the DNA-binding, heterodimerization, ligand-binding, corepressor-binding, and coactivatorbinding motifs of RAR␣. Like wild-type RAR␣, they bind to
retinoic acid-response elements in DNA and, under appropriate
conditions, can activate transcription of RA-target genes.77,80,83,84
However, at physiological levels of retinoic acid, PMLRAR␣ represses rather than activates transcription.85-88 This is
apparently the consequence of enhanced interaction between
PML-RAR␣ and the N-CoR/Sin3/HDAC1 corepressor complex. PML-RAR␣ binds N-CoR at levels of ligand that are
otherwise sufficient to release the corepressor complex from
wild-type RAR␣. By maintaining the promoters of RAresponsive genes in a repressive deacetylated configuration,
PML-RAR␣ suppresses transcription and produces the identical
phenotype to that experimentally produced by a dominantnegative inhibitor of RAR␣.74 Only at pharmacological levels
of ligand does PML-RAR␣ release N-CoR, recruit a coactivator
complex, and allow histone acetylation and chromatin remodeling to proceed. Thus, for PML-RAR␣–expressing APL cells,
pharmacological levels of RA are needed to induce differentiation.
If the end result of PML-RAR␣ binding to the corepressor
complex is active repression of transcription through a HDAC1dependent pathway, then one would predict that the APL
phenotype might be overcome by inhibitors of HDAC. This
prediction has been validated by the finding that RA and
inhibitors of HDAC1 (see below) synergize to induce differentiation of the APL cell line, NB4, or U937 cells engineered to
express PML-RAR␣.85-87 The molecular mechanism underlying
the strong interaction of PML-RAR␣ with N-CoR is not yet
known: there is apparently no direct binding between PML and
N-CoR. Fusion with PML presumably inhibits the ligandinduced conformational changes necessary for release of the
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420
Fig 1. Cartoon of nucleosomal structure. (A) represents the random-coiled tails of the histone octamer intertwined with DNA. (B)
represents the nucleosome with histones acetylated (acetyl groups
drawn as lollipop structures). The acetylated histone tails do not bind
the DNA strands. This allows the DNA to assume a more open
configuration that is accessible to the transcriptional machinery.
N-CoR complex. A similar mechanism may also be at play with
the NPM-RAR␣ t(5;17) fusion, which is also retinoic acidresponsive.89
The t(11;17)(q23;q12) chromosomal translocation of APL
fuses the same sequences of RAR␣ to the N-terminus of
PLZF.79 PLZF is itself a DNA-binding transcription factor,
capable of binding N-CoR via the 120 AA N-terminal POZ
90, 91
motif
(conserved between poxvirus and zinc finger proteins)
retained in the PLZF-RAR␣ fusion.92-94 As a result, PLZFRAR␣ interacts with N-CoR through 2 binding sites: a liganddependent site in the RAR␣ domain and a ligand-independent
site in the PLZF N-terminus.85-88,93 When retinoic acid binds to
the ligand-binding domain of PLZF-RAR␣, the RAR␣ domain
of the fusion protein loses its attraction for N-CoR, but the
PLZF ligand-independent domain continues to bind N-CoR. As
a result, even in the presence of pharmacological levels of
retinoic acid, N-CoR/Sin3/HDAC1 remains tethered to RAresponsive promoters, permanently suppressing transcription
and blocking differentiation. This model explains the lack of
response of t(11;17) patients to ATRA differentiation therapy95
REDNER, WANG, AND LIU
and may explain in part the observation that t(11;17) blasts
show morphologic features indicating less differentiation than
classical APL cells.82 Based on this model, one would predict
that inhibitors of HDAC might partially overcome the suppressive effects of PLZF-RAR␣. This is indeed the case: several
groups have recently demonstrated that inhibitors of HDAC1
synergize with retinoic acid to induce differentiation of otherwise nonresponsive PLZF-RAR␣ cells.85-88
AML1-ETO: Exchanging a coactivator for a corepressor.
The AML1-ETO oncoprotein has recently been shown to alter
gene expression through an analogous mechanism of errant
recruitment of an N-CoR repressor complex. AML1-ETO is
derived from the fusion of the AML1 gene on chromosome
21q22 with the ETO (also called MTG8) locus on chromosome
8q22 (see review by Hiebert et al96). Accounting for over 10%
of acute myeloid leukemias (AML), t(8;21) is seen exclusively
in FAB M2. Patients with t(8;21) have a better response rate to
chemotherapy and a higher remission rate than M2 patients with
normal karyotype.97,98
AML1 is a sequence-specific DNA binding protein that
complexes with core binding factor ␤ (CBF␤) to activate
transcription of target genes.99 Many of the AML1-dependent
genes have been implicated in myeloid maturation, including
interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor
(M-CSF), myeloperoxidase, and neutrophil elastase.96 Unlike
the RAR␣ model discussed in detail above, AML1/CBF␤ binds
no ligand; regulation of AML1 activity occurs as a result of
transcriptional and posttranslational modulation of AML1 (as
yet, these mechanisms have been poorly defined). Recently, it
has been shown that the C-terminus of AML1 interacts with a
p300-containing coactivator complex,100 suggesting that one of
the mechanisms by which AML1 activates transcription is
through local histone acetylation and nucleosomal remodeling.
AML1-ETO, on the other hand, inhibits transcription of
AML1-responsive genes.99,101 AML1-ETO knock-in mice102
have similar embryonic-lethal phenotype as aml1 knock-out
mice,25 which show absent fetal liver hematopoiesis. The
AML1-ETO protein contains the N-terminal 177 AA of AML1,
including the runt homology domain that mediates sequencespecific DNA binding,99 fused to near full-length ETO protein.103 ETO was originally identified through its involvement in
the t(8;21) translocation. Expressed in CD34 cells and in the
brain,104 ETO shares regions of homology with the Drosophila
Nervy protein.103 It contains 2 putative C-terminal Zn-finger
domains, but has not yet been shown to directly interact with
DNA. Little is known about its normal function. It acts as a
transforming oncogene when overexpressed in NIH3T3 cells.105
In tests of its ability to modulate transcription, ETO acts as a
repressor, although it is not yet clear how this relates to the
function of wild-type ETO.36
Recently, our group demonstrated that ETO’s ability to
repress transcription is mediated through its interaction with
N-CoR and recruitment of an N-CoR/Sin3/HDAC1 complex.36
These results have been confirmed by 2 other laboratories.37,38
Because the N-CoR interaction domain maps to the Zn-finger
regions of ETO, a region that is retained in the AML1-ETO
fusion, the same domain likely mediates AML1-ETO’s repressive effects. AML1-ETO mutants that lack this domain lose
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CHROMATIN REMODELING IN LEUKEMIA
421
Fig 2. Fusion proteins in acute promyelocytic leukemia. (A) indicates the unliganded interactions of the RXR/RAR␣ heterodimer with an
N-CoR/Sin3/HDAC1 complex. Upon binding retinoid acid, the RXR/RAR␣ heterodimer releases the corepressor complex and binds a coactivator
complex with histone acetylase activity. (B) indicates the analogous interactions of the RXR/PML-RAR␣ heterodimer with the corepressor
complex. Release of the corepressor complex occurs only in the presence of pharmacological levels of retinoic acid. (C) depicts the
ligand-independent binding of the corepressor complex to PLZF-RAR␣. (It has been proposed, but not yet been formally demonstrated, that
liganded RXR/PLZF-RAR␣ binds both coactivator and corepressor complexes.) Chromatin remodeling occurs only in the presence of both RA and
an HDAC inhibitor.
Fig 3. AML-ETO fusion protein. (A) depicts the association of the
AML1 transcriptional activator with a coactivator complex; (B) indicates the binding of a corepressor to the AML-ETO fusion protein.
Fig 4. MLL-CBP. One of several models for MLL-CBP function. (A)
MLL binds to DNA through interactions between its AT hooks and the
minor groove of DNA. (B) MLL-CBP alters chromatin structure at
MLL-target sites through the action of the histone acetyltransferase
domain of CBP.
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422
their ability to recruit N-CoR and lose their ability to repress
transcription and inhibit differentiation.36,38 The model that has
developed is the following (Fig 3): AML1-ETO binds to AML1
consensus sequences in DNA. Unlike wild-type AML1, the
fusion protein does not initiate p300/CBP-directed histone
acetylation and transcriptional activation. Rather, the opposite
occurs: through its ETO domain, AML1-ETO recruits N-CoR/
Sin3/HDAC1. By permanently tethering this repressive complex to AML1-responsive promoters, AML1-ETO actively
suppresses transcription by maintaining the histones in a
deacetylated conformation and making DNA inaccessible to the
transcriptional apparatus. Inhibition of the expression of AML1responsive genes leads to a block in myeloid development and
leukemic transformation of the maturing hematopoietic progenitors. One might predict that HDAC inhibitors could overcome
the effects of AML1-ETO and lead to reversal of the leukemic
phenotype; preliminary data suggests that this strategy of
chromatin-remodeling therapy holds promise for the treatment
of t(8;21) acute myeloid leukemia (see below).
MLL fusions: A SET of alterations. The MLL locus is
involved in a greater assortment of chromosomal rearrangements in leukemias than any other gene (see recent reviews by
Downing and Look106 and Cimino et al107). Translocations or
inversions of this gene on chromosome 11q23 are associated
with a variety of FAB subtypes and some lymphoid malignancies as well (thus the name, Mixed Lineage Leukemia). Because
of its involvement in the t(4;11) pediatric B-cell acute lymphoblastic leukemia (ALL),108 MLL is also called ALL1. MLL
rearrangement is found in both de novo leukemias and chemotherapy-associated (most often topoisomerase-inhibitor) secondary leukemias. All of the 11q23 leukemias are aggressive,
respond poorly to chemotherapy, and have a poor prognosis.
More than 40 translocation sites have been identified for MLL,
and nearly 20 fusion partners have been cloned. Partial tandem
duplication of MLL with an abnormal MLL/MLL fusion occurs
in AML patients with the (⫹11) karyotype109 and is sometimes
seen in leukemias with normal karyotype. Possibly relating to a
fragile site in the MLL locus, all of the rearrangements cluster
within exons 5-11.110
The MLL gene111-114 is more than 100 kb long, encodes an
11.7-kb transcript with 23 exons,110 and gives rise to a protein of
3972 AA. Clues to the function of MLL have come from the
identification of domains that share homology with other known
proteins. The most significant match is seen in 4 domains that
are conserved with the Drosophila protein Trithorax (TRX),
giving rise to the alternative name for MLL as the human
trithorax gene (HRX or HTRX).111-114 In Drosophila, TRX
positively regulates homeotic gene expression,115-118 which in
turn directs development of embryonic structures. In mammalian hematopoiesis, MLL is thought to regulate expression of
homeobox (HOX) genes,119 which serve a similar critical role as
transcriptional activators of developmentally expressed gene
families. It follows that dysregulation of HOX gene expression
would have global consequences for hematopoietic cells and
give rise to aggressive malignant transformation. As expected,
murine mll ⫺/⫺ knockouts are embryonic lethal.119 Mll ⫹/⫺
animals have numerous developmental skeletal abnormalities,
as well as abnormal hematopoiesis.119
MLL has a series of N-terminal domains known as AT-hooks
REDNER, WANG, AND LIU
and a Zn-finger motif in its C-terminus.111-115 As with other
AT-hook containing proteins, it is thought that the AT-hooks
allow MLL to bind to the minor groove of DNA (Fig 4A).
Although it has not been shown to recognize specific DNA
sequence motifs, TRX does localize to discrete areas of
polytene chromosomes in Drosophila.120 Several of these sites
have been identified as regulatory regions of target genes,
supporting the hypothesis that TRX and MLL associate physically with cis-acting elements of target genes to facilitate their
expression during appropriate stages of development. Unlike
TRX, MLL has an N-terminal region that shares homology with
the regulatory region, but not the catalytic domain, of DNA
methyltransferases112; the significance of this is not yet clear,
although one could speculate that this region might participate
in chromatin structure recognition. Perhaps key to their function, MLL and TRX share a highly conserved C-terminal 150
AA protein interaction domain, known as the SET domain.120
This region is also found in a number of other proteins that have
transcriptional regulatory roles. Through its SET domain, MLL
has been shown to bind INI1 and SNR1, 2 proteins that are
homologous to members of the SWI/SNF complex.120 SWI/
SNF complexes alter chromatin structure in an ATP-dependent
fashion (see above). To date, coprecipitation experiments have
failed to identify MLL or TRX as part of a stable SWI/SNF-like
complex, indicating that the interaction may be a transient
one.120
It is reasonable to speculate that MLL serves as a chromatinbinding protein that serves a regulatory function necessary for
expression of target genes. Through its SET domain, MLL
recruits an SWI/SNF-like ATPase-engine that changes the
nucleosomal structure to maintain an open chromatin conformation. Supporting this hypothesis is the observation that initial
transcription of downstream targets of MLL occurs normally in
mll-null mice; however, in the absence of MLL, transcription of
MLL-target genes cannot be maintained.119
It is difficult to propose a single model that would suggest a
common mechanism for all of the MLL fusion proteins,
including the partial-tandem duplication of MLL itself (Table
3). In all of the MLL fusions (with the exception being the
partial-tandem duplication), the N-terminal AT hooks and
methyltransferase homology domains are retained, but the
C-terminal Zn-finger and SET domains are lost.121 One simple
model is that loss of the ability to recruit the SWI/SNF complex
disrupts MLL function as a regulator of gene expression. In the
tandem MLL duplication, in which the SET domain is preserved, one might postulate that the altered MLL conformation,
and the abnormal distance of the SET domain from the
N-terminal AT-hooks, might render the MLL protein nonfunctional.
However, the picture for 11q23 rearrangements is likely not
Table 3. MLL Fusion Proteins That May Affect Chromatin
Remodeling
Fusion
Karyotype
Potential Target Pathway
All MLL-fusions
MLL-AF9
MLL-ENL
MLL-CBP
MLL-p300
Any 11q23 abnormality
t(9;11)(p22;q23)
t(11;19)(q23;p13.3)
t(11;16)(q23;p13)
t(11;23)(q23;q13)
SWI/SNF
SWI/SNF
SWI/SNF and/or HAT
HAT
HAT
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CHROMATIN REMODELING IN LEUKEMIA
so simple. Two of its fusion partners,122 AF9 in t(9;11)(p22;q23)
and ENL in t(11;19)(q23;p13.3), are homologous to proteins
that are themselves associated with the SWI/SNF complex.123
Fusion with the DNA-binding AT-hook domain of MLL might
result in permanent tethering of a SWI/SNF-like complex to
MLL targets, resulting in constitutive activation of the SWI/
SNF chromatin remodeling complex. Another speculative model
is that the fusions disrupt MLL-target chromatin structure
through recruitment of histone acetylase enzymes. For example,
ENL contains a transcriptional activation domain that is retained in the MLL-ENL fusion. Through its activation motif,
ENL might tether an HAT-containing coactivator complex to
MLL target genes.
Switching HATs. Two other MLL-fusions potentially act
through a similar gain-of-function mechanism involving histone acetylase complexes: t(11;16)(q23;p13) and t(11;23)(q23;
q13) fuse the upstream sequences of MLL to CBP124-126 and
p300,127 respectively. Most of the domains of CBP and p300 are
retained, including those that bind other components of the
coactivator complex, as well as the catalytic domain that
encodes histone acetylase activity (Fig 4B). For these fusions it
is likely that abnormal chromatin remodeling occurs either
though constitutive activation of HAT activity or through
recruitment of other acetyltransferase components of the coactivator complex.
Histone acetylases are also mutated in the t(8;16)(p11;p13)128
and inv(8)(p11;q13)48 chromosomal rearrangements associated
with M4 and M5 AML. In the first, CBP is fused to upstream
elements of a gene called MOZ.128 MOZ itself has predicted
acetyltransferase activity, although its targets and biological
function have not yet been determined. MOZ contains a variant
Zn-finger but has not been shown to bind DNA. In the
MOZ-CBP fusion the Zn-finger and catalytic domain of MOZ
are fused to almost the entire CBP protein. The breakpoint in
CBP is similar to that seen in the MLL-CBP fusion (see above).
MOZ-CBP therefore has 2 HAT activities.
Similarly, the inv(8) rearrangement fuses the upstream sequences of MOZ to TIF2.48 TIF2 is a homologue of p/CIP, a
component of the CBP/p300 coactivator complex. The domain
of p/CIP that mediates direct interaction with nuclear hormone
receptors is lost in the MOZ-fusion, but the CBP-interaction
domain is retained. TIF2 itself is predicted to have acetyltransferase activity, and, like MOZ-CBP, MOZ-TIF2 retains the
acetyltransferase homology domains from each of the fusion
partners.48 Like the MOZ-CBP rearrangement, such fusion
proteins might result in altered chromatin remodeling of MOZ
targets either through a dominant-negative effect, altered substrate specificity of the fusion enzyme, or recruitment of a
HAT-containing coactivator complex to MOZ targets. Any of
these mechanisms might impair normal chromatin remodeling,
leading to aberrant transcription. It is worth noting that the
MOZ-CBP t(8;16) and MOZ-TIF2 inv(8) leukemias have virtually identical FAB M5 phenotypes,48,128 suggesting that the 2
fusions have a similar final common pathway.
CHROMATIN THERAPY
Excitement in the field of chromatin structure has been
generated with the realization that remodeling mechanisms
might be targeted in therapeutic strategies. Preliminary studies,
423
mostly in the in vitro setting, have focused on inhibition of
histone deacetylase, in part because HDAC1 was one of the first
enzymes identified in nucleosomal remodeling, because its
function is best understood, and because it is the only candidate
for which specific inhibitors have been identified.
Butyric acid, or butyrate, a physiologic byproduct of colonic
bacterial fermentation, was the first identified of the HDAC
inhibitors.129-131 It functions as a competitive inhibitor of
HDAC, perhaps by mimicking the normal substrate (butyrate is
a 4-carbon molecule, whereas acetyl groups are 2-carbon). In
micromolar concentrations, butyrate is not specific for HDAC:
it also inhibits phosphorylation and methylation of nuclear
proteins as well as DNA methylation. Its analog phenylbutyrate132,133 acts in a similar manner.
More specific for HDAC than butyrate or its analogs are
trichostatin A134,135 (TSA) and trapoxin136,137 (TPX). TSA, a
product of Streptomyces hygropicus, was originally isolated as
an antifungal agent. TPX, a cyclic tetrapeptide containing 2
L-phenylalanines, was identified in screens of fungal metabolites that induced morphological reversion of transformed
NIH3T3 cells.138 TPX and TSA have emerged as potent
inhibitors of the histone deacetylases. TSA reversibly inhibits,
whereas TPX irreversibly binds to and inactivates the HDAC
enzyme. TSA inhibits histone deacetylation with a Ki of 3.4
nmol/L,135 about 1,000-fold less than butyrate; TPX is even
more potent. Unlike butyrate and its analogs, nonspecific
inhibition of other enzyme systems has not yet been reported for
TSA or TPX. To date, no data are available on the pharmacokinetics or pharmacodynamics of TSA or TPX. Besides TSA,
TPX, and butyrate and its derivatives, a number of hybrid polar
compounds139,140 have been found to potently inhibit HDAC
enzymes, such as suberoylanilide hydroxamic acid and mcarboxycinnamic acid bishydroxamide. Tributyrin,141 a triglyceride with butyrate molecules esterified at the 1, 2, or 3
positions, holds potential as a long-acting, orally administered
prodrug.
A major issue concerning the use of such HDAC inhibitors is
the potential for modulating chromatin of genes that are not
involved in the leukemia or genes in nonleukemic bystander
cells. As discussed above, the translocations that cause HDAC
to function in inappropriate ways do not truly alter the enzyme
itself, but rather bring the normal enzyme into a chromatin
environment that it would not otherwise contact. Would HDAC
inhibitors have unwanted nonspecific effects that disrupt chromatin of all genes in a cell? Although the explanations are not
yet apparent, experience in multiple tissue culture systems has
suggested that the effects of HDAC inhibitors are limited.
Butyrate, at doses that should inhibit HDAC enzymatic activity,
does not kill cells.129 However, the nonspecific effects of
butyrate on phosphorylation and methylation make it difficult to
draw definite conclusions as to the contribution of HDAC
inhibition to its biological effects. TSA has been used in a
number of in vitro settings: it was first shown to induce
differentiation of MEL cells,142 without having significant
apoptotic or transforming effects on the cells. TSA inhibition of
HDAC has been shown to increase acetylation of only a subset
of promoters,143 suggesting that a minority of genes are
regulated through HDAC-dependent chromatin remodeling
mechanisms. The observation of normal ordered differentiation
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
424
in APL model systems with a variety of HDAC inhibitors85-88
supports the notion that these agents do not have global effects
on chromatin structure and gene expression.
HDAC inhibitors in leukemia. We have already alluded to
the relationship between RA responsiveness, the HDAC complex, and the RAR␣-fusion proteins in APL. APL has become
the paradigm for the application of HDAC inhibitors. As
described above, HDAC inhibitors synergize with retinoic acid
to overcome the PML-RAR␣ and PLZF-RAR␣ induced maturation blockade in cell models.85-88 Pandolfi’s group87 has shown
that, similar to patients with APL, PML-RAR␣ transgenic mice
responded to RA treatment, whereas PLZF-RAR␣ transgenic
mice developed RA-resistant leukemia. In vitro, neither RA nor
TSA had significant effects on the PLZF-RAR␣ blasts, but
together they induced differentiation. The interpretation of this
data is that RA alone failed to release the N-CoR/Sin3/HDAC1
complex from PLZF-RAR␣; that TSA acted downstream to
inhibit the HDAC complex, but did not induce recruitment of a
coactivator complex; and that only in the presence of both
molecules could the suppressive effects of PLZF-RAR␣ be
overcome. These studies are consistent with other reports that
suggest that HDAC inhibitors might have a role in APL
therapy.85-88 The recent report of blast-cell differentiation and
successful remission induction in a patient with PLZF-RAR␣
treated with a combination of ATRA and granulocyte colonystimulating factor (G-CSF)144 raises speculation as to whether
G-CSF might alter HDAC activity.
Besides PLZF-RAR␣ blasts, some PML-RAR␣–expressing
APL cells do not respond to RA alone but may differentiate in
response to the combination of RA and an HDAC inhibitor.
Several patient samples have been identified to have mutations
in the C-terminal region of PML-RAR␣, near the N-CoR
binding domain.145 Warrell’s group at Memorial SloanKettering has attempted to capitalize on such in vitro observations, reporting the use of the HDAC inhibitor phenylbutyrate in
a PML-RAR␣ patient who was in her third relapse.146 She had
previously been induced with ATRA and chemotherapy, treated
in first remission with ATRA and allogeneic bone marrow
transplantation, and treated in second relapse with arsenic
trioxide after failing reinduction with ATRA or standard chemotherapy. After 11 days on ATRA at 45 mg/m2/d, no change was
observed in her bone marrow. At that time, phenylbutyrate was
added to her regimen at a dose of 150 mg/kg/d. Immunofluorescence and Western blot analysis of blood and bone marrow
mononuclear cells documented a time-dependent increase in
histone acetylation (presumably as a result of antagonization of
HDAC). Over the next 3 weeks, the doses of both ATRA and
phenylbutyrate were increased to 90 mg/m2/d and 210 mg/kg,
respectively. A bone marrow performed 2 weeks after the
addition of the phenylbutyrate showed a decrease in the
percentage of leukemic cells from 23% to 9%. A bone marrow
10 days later showed elimination of leukemic blasts. After a
second course of therapy, she achieved a molecular remission
(PML-RAR␣ negative) and continued to be in remission after 6
months.
Aside from APL, HDAC inhibitors have a potential role in
the treatment of AML1-ETO AML (see above). We and others
have proposed that AML1-ETO’s leukemic potential is mediated by the recruitment of an HDAC-containing complex to
REDNER, WANG, AND LIU
AML1-responsive promoters.36-38 In our own experiments,147
we found that TSA or phenylbutyrate was able to partially
reverse transcriptional repression mediated by the ETO moiety
of AML1-ETO. In vitro treatment of an AML1-ETO cell line
(Kasumi-1) with clinically attainable levels of phenylbutyrate
induced partial differentiation and apoptosis. Such results may
herald the therapeutic application of HDAC inhibitors for
t(8;21) AML in the future.
The clinical use of HDAC inhibitors need not be limited to
patients with obvious abnormalities in histone deacetylation
pathways. In 1983, continuous infusion of butyrate, at a dose of
500 mg/kg/d, was reported to induce a partial remission in a
patient with myelomonocytic leukemia.148 No chromosomal
abnormalities were noted in this case. It is possible that this
patient did have an unrecognized rearrangement that would
have aberrantly recruited a histone deacetylase to an abnormal
target or that inhibition of HDAC may have compensated for an
underactive HAT. Alternatively, the effects might not have been
related to fusion gene-specific effects. For example, phenylbutyrate has been reported to upregulate the B7 costimulatory
molecule on AML blasts,149 suggesting a role in immune
surveillance.
These exciting results with HDAC inhibitors invigorate the
search for other means of modulating chromatin remodeling.
Despite the current dearth of specific inhibitors of HAT and
SWI/SNF enzymes, the development of inhibitory peptides is a
potential avenue that has yet to be pursued. Thanks to insights
gained from studies of the molecular biology of leukemia,
chromatin therapy may emerge as a potent antileukemia strategy of the future.
ACKNOWLEDGMENT
The authors thank Daniel E. Johnson, Margaret V. Ragni, and Richard
A. Steinman for critical reading of the manuscript and Neal Young for
encouragement and support.
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1999 94: 417-428
Chromatin Remodeling and Leukemia: New Therapeutic Paradigms
Robert L. Redner, Jianxiang Wang and Johnson M. Liu
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