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Introduction
Leukemia is one of the most notorious enemies of
mankind and accounts for some 300 000 new cases and 222 000
deaths each year worldwide. It is the leading cause of
cancer death among men under 40 years and among women
under 20 years[1]. This high ratio of deaths/cases (74%)
reflects the unsatisfactory prognosis of leukemia with current
therapeutics, mainly composed of chemotherapy. Therefore,
the development of new therapeutic approaches for leukemia
patients is still an urgent need for scientists/hematologists,
while dissection of leukemia pathogenesis is critical to the
development of molecularly targeted therapies that might have
maximal therapeutic efficacies with minimal adverse effects.
Recognition of leukemia: from morphological change to molecular markers
Leukemia represents a group of hematological
malignancies characterized by clonal expansion of hematopoietic cells
with uncontrolled proliferation, decreased apoptosis and
blocked differentiation. According to the disease
progression and hematopoietic lineages involved, leukemia can be
divided into acute or chronic, lymphoid or myeloid, with a
number of additional subtypes based on the distinct stages
of differentiation block along with each
lineage[2]. Acute myelogenous leukemia (AML), the most common leukemia
diagnosed in adults, is a malignant disease of the bone
marrow in which hematopoietic precursors are arrested in an
early stage of myeloid development. AML leukemic cells
can be identified in most instances by the presence of Auer
rods, myeloperoxidase or monocyte-associated esterases,
and AML can be divided into M0_M7 subtypes. Most
subtypes are distinguished from other related blood disorders
by the presence of more than 20%_30% blasts in the bone
marrow. In contrast, acute lymphoid leukemia (ALL) is the
most common cancer in childhood and leukemic
lymphoblasts lack specific morphological or cytochemical features.
After three decades of rapid advances, leukemia research
has generated a rich and complex body of knowledge,
revealing leukemia to be a disease of hematopoietic
stem/progenitor cells that involves dynamic changes in the
genome. Recurrent chromosomal changes occur in more than
half of all cases of leukemia, and more than 300 chromosomal
translocations have been detected so far. The pathogenesis
of AML involves an array of molecular alterations that
disrupt almost every facet of cell transformation. These
processes include the regulation of cell proliferation,
differen-tiation, self-renewal, survival, cell cycle checkpoint control,
DNA repair and chromatin stability, and cell
dissemination[3]. A vastly improved understanding of ALL pathophysiology
has emerged from two decades of progress in defining the
lineage-related development, antigen expression and genetic
abnormalities of leukemic cells, and in elucidating the
multistep mechanisms by which changes in the function of
specific genes disrupt key signaling pathways, which ultimately
lead to leukemic transformation[4]. Tremendous advances in
the elucidation of cytogenetic and molecular genetic
abnormalities of major AML and ALL subtypes (Table 1) have not
only enabled the classification of leukemia into
progno-stically and therapeutically important distinct clinical entities,
but have also identified candidate molecules for targeted
therapeutics of AML and ALL.
AML: recent advances
AML is a very heterogeneous disease with regard to
clinical features and acquired genetic alterations, both those
detected microscopically as structural and numerical
chromosome aberrations, and those detected as submicroscopic
gene mutations and changes in gene expression. In addition,
the responses of AML to therapies differ from one subtype
to another. Thus, to improve clinical outcome, the
therapeutic strategies should be disease pathogenesis-based and
individualized.
APL: from disease pathogenesis to targeted therapies
APL is characterized by the presence of an accumulation
of abnormal promyelocytes in bone marrow or peripheral
blood that do not differentiate into mature granulocytes, the
occurrence of fibrinogenopenia and disseminated
intravascular coagulation that is often worsened by chemotherapy,
and the presence of the specific chromosomal translocation
t(15;17)(q22;q21) or its variants[5].
t(15;17) and PML-RARα fusion gene Molecular
cloning and sequence analysis of the genes involved in
t(15;17) are critical for our understanding of the
pathogenesis of APL and the differentiation and apoptosis therapies
for this subtype of AML. Chen et
al[6] reported that rearrangements in the second intron of
the RARα gene on chromosome 17 are present in a large majority of APL patients
and the 5' part of the RARα gene has been shown to be
frequently disrupted in Chinese patients with
APL[26]. On chromosome 15, rearrangements of the MYL (named PML later)
gene and a breakpoint cluster region as well as some
molecular variants have been
reported[27]. The entire PML
genomic gene has been cloned and its exon-intron structure
has also been established[28,29].
It is well established that the chromosomal translocation
t(15;17) disrupts the PML gene on chromosome 15 and the
RARα gene on chromosome 17, resulting in chimeric
PML-RARα and RARα-PML fusion
genes[30,31]. To characterize the expression patterns of the
PML-RARα fusion gene, a sensitive reverse transcriptase-polymerase chain reaction
(RT-PCR) procedure was established and was used to
analyze the PML-RARα chimeric mRNAs in patients with
APL[32,33]. Three distinct types of
PML-RARα transcripts, long (L), short
(S) and variant (V), were identified. Recently, a
real-time RT-PCR system was established to quantify the dose
of PML-RARα fusion transcripts in APL patients at distinct
disease stages and this system was useful in reflecting
leukemic burden, assessing response to treatment and indicating
the ultimate clinical outcome or curability of
disease[34].
To gain further insights into the molecular basis of
t(15;17), Gu et al[35]
sequenced the entire genomic DNA region
of RARα. All previously reported "spacer" sequences in
V-type transcripts[36] were found
in intron 2 of the RARα gene
and most of these sequences were flanked
by gt splice
donor sites. Two cases with a relatively long spacer
sequ-ence showed resistance to RA treatment. In these cases, the
aberrant V-type PML-RARα protein displayed increased
affinity to the nuclear corepressor protein SMRT, providing
further evidence that RA exerts a therapeutic effect on APL
through modulation of the
RARα_corepressor interaction. Among patients with the L-type or S-type
PML-RARα
fusion transcript, some consensus motifs were identified at
the hotspots of the chromosome 17q breakpoints within
intron 2 of _RARα, strengthening the importance of this intron
in the pathogenesis of APL.
t(11;17)(q23;q21) and PLZF-RARα fusion
gene A subset of APL cases were shown to present atypical phenotypic,
cytogenetic or molecular features at different stages of the
disease[37]. In 1993, Chen
et al[38] reported an unusual
karyotype 46, XY, t(11;17)(q23;q21) and showed a rearrangement
between the RARα gene and a newly
discovered promyelocytic leukemia zinc finger
(PLZF) gene. Chen et al[39]
demonstrated that the PLZF gene encodes a potential transcription
factor containing nine zinc finger motifs related to the
Drosophila gap gene Kruppel and is expressed as at least two
isoforms that differ in the sequences encoding the
N-terminal region of the protein. The PLZF
gene was 201-kb long and contained six
exons and five introns. At least four
alternative splicings (AS-I, -II, -III, and -IV) were found within
exon 1. These alternative splicings maintained the open
reading frames (ORF) and may encode isoforms
with an absence of important functional domains. A
TATA box and several transcription factor binding sites were found in the putative
promoter region upstream of the transcription
start site[40]. Like the
PML-RARα protein, PLZF-RARα inhibits ligand-dependent transactivation of
RARα, reflecting the "dominant negative" effect of
PLZF-RARα on wild-type RARα and implicating the
PLZF-RARα fusion protein in the molecular pathogenesis of
APL[41].
Variant chromosomal translocations were also identified
in APL, that is, t(5;17)(q35;q21) generating
NPM-RARα,
t(11;17)(q13;q21) resulting in NuMA-RARα and
dup(17)(q11;q21) with generation of Stat5b-RARα
fusions[42].
APL murine models Transgenic mice were
generated to study the leukemogenic potential of the fusion
genes in vivo. Mice expressing the human cathepsin G
(hCG)-PML-RARα transgene were found to have altered myeloid development
that was characterized by increased percentages of
immature and mature myeloid cells in the peripheral blood, bone
marrow and spleen. In addition, approximately 30% of
transgene-expressing mice eventually developed acute
myeloid leukemia after a long latent
period[43]. Cheng et
al[44] generated transgenic mice with
PLZF-RARα and NPM-RARα.
PLZF-RARα transgenic animals developed chronic myeloid
leukemia (CML)-like phenotypes, whereas
NPM-RARα transgenic mice showed a spectrum of phenotypes from
typical APL to CML. In contrast to bone marrow cells from
PLZF-RARα transgenic mice, those from
NPM-RARa transgenic mice could be induced to differentiate by all-trans retinoic
acid (ATRA). Dissociation of SMRT from different
receptors was also observed at different concentrations of ATRA
for RARα-RXRα, NPM-RARα and
PML-RARα, but was not observed in
PLZF-RARα. These data clearly establish the
leukemogenic role of PLZF-RARα and
NPM-RARα and the importance of fusion receptor/corepressor interactions in the
pathogenesis as well as in determining different clinical
phenotypes of APL. Recently, RARα-PLZF and
PLZF-RARα/RARα-PLZF double transgenic mice have also been
generated[45].
Mechanisms of retinoic acid and arsenic
treatment APL is the first example of a human cancer that can be effectively
treated with the differentiation inducer ATRA, a derivative
of vitamin A[14]. Nevertheless, arsenic trioxide (ATO) has
been shown in China to have a strong therapeutic effect
against APL through induction of apoptosis at high concentra-
tion and partial differentiation at low
concentration[15,16,46_49]. Modulation and degradation of
PML-RARα fusion protein can be induced by both ATRA and ATO, demonstrating that
APL is the first leukemia in which targeted therapy has
proven to be effective[5,42,50_56]. Under a pharmacological
con-centration (10-7_10-6 mol/L) of ATRA, the corepressors and
histone deacetylase (HDAC) were released from the
PML-RARα homodimer, while co-activator and histone acetylase
were recruited, resulting in the relief of transcriptional
repression. It has been shown that although the interaction
with corepressors and HDAC of the RARα moiety in
PLZF-RARα was modulable under 10-6 mol/L ATRA, binding to the
corepressor complex on the N-terminal POZ domain of the
PLZF moiety was retained even under a very high ligand
concentration (10-5 mol/L). As a result, ATRA alone cannot
induce maturation of PLZF-RARα-harboring cells, whereas
HDAC inhibitor is required to cooperate with ATRA to
induce differentiation of these
cells[36]. More recently, proteolysis of
PML-RARα via different pathways has drawn considerable attention. Although it was reported that ATRA
could trigger caspase-mediated cleavage of the
PML-RARα chimeric protein on PML[57], further dissecting of the
pathways involved in PML-RARα catabolism led to the
discovery of ubiquitin/proteasome system (UPS)-mediated
degradation of PML-RARα and RARα, which was dependent on
the binding of SUG-1 in the AF2 transactivation domain of
RARα with 19S proteasome[58,59]. The degradation of
PML-RARα contributes to the restoration of normal retinoid
signaling and PML-NB functions, although this event seems to
be relatively late compared to the modulation of chimeric
protein transregulatory activity. ATRA also induces cAMP,
a differentiation enhancer that boosts transcriptional
activa-tion, reverses the silencing of the transactivating function
of RXR, restores ATRA-triggered differentiation in
mutant ATRA-resistant cells[60] and inhibits cell growth by
modulating several major players in G(1)/S transition
regulation. Garzon et al[61] demonstrated that ATRA
treatment of APL patients and cell lines modulates a small
number of micro-RNAs (miRNA), most of which have confirmed
targets involved in hematopoietic differentiation and
apoptosis. They found that along with miR-223, miR-107
negatively regulated NFI-A; ATRA induced NF-κB bond to
the promoter of let-7a-3 and activated its transcription; and
ATRA down-regulation of RAS and Bcl-2 correlated with
the activation of two confirmed miRNA regulators of these
genes, let-7a- and miR-15a/miR-16-1, respectively. Systems
analysis of transcriptome and proteome in ATRA-induced
APL cell differentiation reveals induction of an array of
transcription factors and cofactors, activation of calcium
signaling, stimulation of the IFN pathway, activation of the
UPS necessary for degradation of the PML-RARα and
restoration of the PML-NB, cell cycle arrest, induction of
cyclooxygenase 1[62], inhibition of
angiogenesis[63], down-regulation of tissue
factor[64], and a gain in apoptotic potential.
Of note, a number of novel genes, RA-induced genes (RIG,
such as RIG-G, E, K, and I), have been cloned at the
Shanghai Institute of Hematology and have been shown to have
very interesting functional
features[65_69].
The cysteine-rich region of the PML protein sequence is
a principal candidate for interaction with trivalent arsenic.
ATO induces modulation and catabolism of the
PML-RARα fusion protein in a pattern that differs from that induced by
ATRA. ATO treatment causes APL cells to experience a
series of changes, including reaggregation of PML-NB
antigens, recruitment of PML-RARα proteins onto NB and
degradation of PML-RARα[70]. That ATO targets the PML
moiety of PML-RARα is supported by the observation that
a similar modulation process of wild-type PML, but not
RARα, occurs in APL or non-APL cells. Through a yet
unknown mechanism, ATO causes PML to be located to the
nuclear matrix and sumoylated at two important residues
resulting in different consequences, that is, sumolyation at
K160 necessary for 11S proteasome recruitment and
subsequent sumolyation at K490 for nuclear localization and
degradation[71,72]. ATO treatment also induced phosphorylation
of the PML protein through a mitogen-activated protein
(MAP) kinase pathway[73].
A striking similarity in the effect of the two otherwise
unrelated agents, ATRA and ATO, is the degradation of
PML-RARα oncoprotein through distinct
pathways[5,42,74]. Intriguingly, a clearance of
PML_RARα transcript in an earlier and more thorough manner, and higher-quality
remission and survival in newly diagnosed APL are achieved when
ATRA is combined with ATO compared with either monotherapy, making APL a curable
disease[75,76]. To gain insights into the synergic effects of the ATRA/ATO
combination on APL cells, systems analysis of transcriptome and
proteome has been carried out in RA/ATO-induced cell
differentiation/apoptosis. Zheng et
al[77] reported that at an early state (within 6 h), ATRA plus ATO modulated
transcription factors/cofactors associated with myeloid-specific
gene expression, nuclear receptor signaling molecules,
interferon pathway members and factors involved in some
other cascades. At a time point of 12_24 h,
ATRA/ATO-regulated genes/proteins seemed to be an amplification of
RA signaling and a strong activation of the
ubiquitin/proteasome system, which might facilitate degradation of
PML-RARα. After 48_72 h of treatment with RA/ATO, the
expression of the differentiation markers and functional
molecules reached a maximum, whereas genes/proteins
promoting cell cycle or enhancing cell proliferation were
significantly repressed. As the cells approached terminal
differen-tiation, the expression of apoptosis agonists increased
gradually. Recently Leung et
al[78] reported that treatment with ATRA led to a dose-dependent increase in
aquagly-ceroporin 9 (AQP9) gene transcription and protein
expres-sion, which in turn increased arsenic uptake into the cells.
These processes might contribute to the mechanisms of
ATRA/ATO-induced differentiation/apoptosis of APL cells.
AML M2 with t(8;21)
AML M2, or myeloblastic leukemia with maturation, is
one of the most common types of AML and occurs in about
25% of all cases. A characteristic translocation observed in
AML M2 is t(8;21). Treatment includes intensive multidrug
chemotherapy and in selected cases allogeneic bone
marrow transplantation. Nevertheless, the outcome for AML
M2 patients remains poor with an overall survival of
35%_60%[79]. Children with AML M2 carrying the t(8;21)
translocation have a better prognosis (69% survival). New
therapeutics are required to increase the probability of cure in this
serious disorder.
Translocation t(8;21) and resultant AML1-ETO
fusion The t(8;21)(q22;q22), where coding sequences of the
AML1 gene on chromosome 21 are juxtaposed to coding
sequences of the ETO gene on chromosome 8, generating
an AML1-ETO (AE) fusion transcript, is seen in 40%_80%
of AML M2 and 12%_20% of all cases of
AML[80,81], and represents the most common chromosomal translocation
in AML[80,82]. The AE fusion protein recruits the
N-CoR-mSin3_HDAC complex[83,84], inhibits transcription of
AML1 target genes[80,83], including interleukin-3
(IL-3)[85] and granulocyte-macrophage colony-stimulating factor
(GM-CSF)[86,87], activates transcription of apoptotic
antagonist Bcl-2[88], upregulates protein tyrosine kinase
C-KIT[7], induces the expression of granulocyte colony-stimulating
factor receptor (G-CSFR) as well as myeloperoxidase
(MPO)[89], and blocks transactivation of the GM-CSF
promoter[87]. The AE oncoprotein enhances self-renewal of
hematopoietic stem/progenitor cells, blocks hematopoietic
differentiation, disturbs normal cell
proliferation[82] and
immortalizes murine hematopoietic
progenitors[90,91].
Although reports suggest that additional mutations are
required to cooperate with AE to cause murine full-blown
leukemia[90,92], stem cells expressing AE induce a
myeloproliferative disorder[93] or distinct myeloid developmental
abnormalities in mice[94], while deletion of a C-terminal
NcoR/SMRT-interacting region strongly induces leukemia
development[95]. Recently, a novel isoform of the AE transcript,
AML1-ETO9a (AE9a), which includes an extra exon 9a of the ETO
gene and encodes a C-terminally truncated AE protein, was
identified from human t(8;21) AML and was shown to
rapidly induce leukemia in a mouse retroviral
transduction_transplantation model[17]. These data demonstrate that AE plays
a critical role in the pathogenesis of t(8;21) leukemia and that
AE-targeting agents might be helpful for the treatment of
t(8;21) AML.
Abnormalities of receptor tyrosine kinases in
t(8;21) AML To further explore the genetic abnormalities in AML
M2 with t(8;21), Wang et al[7] screened a number of
candidate genes and identified 11 types of mutations in the C-KIT
gene (mC-KIT), including 6 previously undescribed ones,
among 26 of 54 (48.1%) cases with t(8;21). To address a
possible chronological order between AE and mC-KIT, we
showed that among patients with AE and mC-KIT most
leukemic cells at disease presentation harbored both genetic
alterations, whereas in three cases investigated during
complete remission, only AE, but not mC-KIT, could be detected
using allele-specific PCR. Therefore, mC-KIT should be a
subsequent event on the basis of t(8;21). Furthermore,
induced expression of AE in U937-A/E cells significantly
upregulated mRNA and protein levels of C-KIT. This may
lead to an alternative way of C-KIT activation and may
explain the significantly higher C-KIT expression in 81.3% of
patients with t(8;21) compared with patients with other
leukemias. These data strongly suggest that t(8;21) AML
follows a stepwise model in leukemo-genesis, that is, AE
represents the first fundamental genetic hit to initiate the
disease and activation of the C-KIT pathway may be the
second, but also crucial, hit for the development of a
full-blown leukemia.
Schessl et al[96] reported that AE occurred frequently
together with activating mutations involving signal
transduction pathways in patients with AML. To characterize
genetic alterations that occur together with the AE fusion
gene in AML, 135 patients with AE (93 men, 42 women;
median age 50.9 years, range 15.8_89.1 years) were screened
for activating mutations in the receptor tyrosine kinases FLT3
and C-KIT, as well as in NRAS (KITD816, NRAS codon
12/13/61). Patients included 118 with newly diagnosed AML, 4
in first relapse and 13 classified as having therapy-related
AML. Activating mutations were detected in 38 patients
(28.1%) and included mutations in the receptor tyrosine
kinase FLT3 or C-KIT (25 patients in total) or in NRAS (13
patients). In contrast, no MLL-partial tandem duplication
(MLL-PTD) mutations were detected in 87 samples subjected
to this analysis. These data demonstrated that genetic
alterations occurring with the AE fusion gene frequently affect
signal transduction pathways.
Murine models for AML M2 The AE knock-in mice and
transgenic mice using MRP promoter, a
tetracycline-inducible system or Cre/LoxP system and lethally irradiated mice
reconstituted by AE-expressing HSPC do not develop any
malignancies[90,92,97,98] or
leukemia[94,99], whereas Fenske et
al[93] reported that targeted expression of the AE in mice using the
Ly6A (Sca1) locus induces a spontaneous
myeloproliferative disorder (MPD). With the presence of additional
mutations, for example, mutagen N-ethyl-N- nitrosourea
(ENU), introduced mutations or coexpression of
TEL-PDGFRβ fusion gene, exogenous AE-expressing mice
develop an AML phenotype[90,92,100]. Schessl
et al[96] reported that AE collaborated with FLT3-length mutation to induce
acute leukemia in a murine BM transplantation model.
These data strongly suggest that additional genetic
alterations are required to cooperate with full length AE in
inducing leukemia.
To investigate the nature of the secondary mutations
required for AE-mediated leukemogenesis, Yan et
al[95] carried out bone marrow transplant experiments by using
hematopoietic cells infected with an AE-expressing retrovirus.
Interestingly, they found that in the absence of any
artificially induced mutations, one mouse rapidly developed AML
14 weeks after the bone marrow
transplantation[95]. A surprising finding that emerged from this study was that,
because of a 1-bp insertion, the leukemic cells expressed a
C-terminal 200-aa truncated form of AE (AEtr) lacking a
critical domain for NCoR/SMRT and ETO interaction. Unlike its
full-length counterpart, the expression of AEtr resulted in a
rapid onset of leukemia in transplantation-recipient mice. The
associated growth-arrest function of AE was lost with AEtr.
In addition, the regulation of cell-cycle regulatory proteins,
such as cyclin D3, cyclin A, CDK4, and CDK inhibitors
p21WAF1/CIP1 and p27KIP1, by AE and C-terminal
truncated AE were opposed. These results indicated that
disruption of molecular events relating to the function of the
AE C-terminal NCoR/SMRT interacting domain promoted the
onset of t(8;21)-involved leukemogenesis and offered a
paradigm to the study of genetic events related to cancer
development. Recently, Yan et
al[17] reported the identification of a previously unknown alternatively spliced
isoform of the AE transcript, AML1-ETO9a (AE9a), that
included an extra exon, exon 9a, of the ETO gene. AE9a
encodes a C-terminally truncated AE protein of 575 amino acids.
Expression of AE9a leads to rapid development of leukemia
in a mouse retroviral transduction_transplantation model.
More importantly, coexpression of AE and AE9a results in
the substantially earlier onset of AML and blocks myeloid
cell differentiation at a more immature stage. These results
indicate that fusion proteins from alternatively spliced
isoforms of a chromosomal translocation may work together
to induce cancer development.
Potential targeted therapies for t(8;21)
AML Clinically, aggressive cytosine arabinoside (Ara-C)-based
chemotherapy is the standard protocol for t(8;21) AML, and t(8;21)
has been shown to be a favorable prognostic factor for
AML[101]. However, other researchers have demonstrated that
the median survival time of patients with
t(8;21) AML is less than 2 years with a 5-year survival rate of
no more than 40%[7,102_106]. To further improve the clinical
outcome and to provide therapeutic options for t(8;21)
AML patients, investigational therapy should be developed.
Zhou et al[11] reported that oridonin, a diterpenoid extracted
from the medicinal herb Rabdosia rubescens, induced
apoptosis of t(8;21) AML cells. Intriguingly, the t(8;21)
product, AE fusion protein that plays a critical role in
leukemogenesis, was degraded with generation of a
catabolic fragment, whereas the expression pattern of the AE
target genes investigated could be reprogrammed. The
ectopic expression of AE enhanced the apoptotic effect of
oridonin in U937 cells. Pre-incubation with caspase
inhibitors blocked oridonin-triggered cleavage of AE, whereas
substitution of Ala for Asp at residues 188 in the ETO moiety of
the fusion abrogated AE degradation. Furthermore, oridonin
prolonged the lifespan of C57 mice bearing truncated
AE-expressing leukemic cells without suppression of bone
marrow or reduction of body weight of animals, and exerted
synergic effects when combined with cytosine arabinoside.
Oridonin also inhibited tumor growth in nude mice
inoculated with t(8;21)-harboring Kasumi-1 cells. These results
suggest that oridonin may be a potential anti-leukemia agent
that targets AE oncoprotein at residue D188 with low
adverse effects, and may be helpful for the treatment of
patients with t(8;21) AML. Furthermore, a
genotype_phenotype correlation was revealed in terms of the response to
tyrosine kinase inhibitor Gleevec/Imatinib meslate/STI571,
in that the drug suppressed the C-KIT activity and induced
proliferation inhibition and apoptosis in t(8;21) leukemic cells
bearing the C-KIT N822K mutation or C-KIT overexpression,
but not in cells with mC-KIT at residue D816. Gleevec also
exerted a synergic effect on apoptosis induction with
cytarabine, providing a potential use in the treatment of
t(8;21) leukemia[7]. Yang et
al[13] showed that AE undergoes degradation in response to treatment with histone
deacety-lase inhibitors, one of which, depsipeptide (DEP), is
currently undergoing Phase II clinical testing in a variety of
malignancies. These compounds induce turnover of AE
without affecting the stability of AE partner proteins. In addition,
AE physically interacts with heat shock protein 90 (HSP90).
DEP treatment interrupts the association of AE with HSP90
and induces proteasomal degradation of AE. DEP and the
HSP90 antagonist 17-allylamino-geldanamycin (17-AAG)
both triggered AE degradation, but without any additive or
cooperative effects. These findings may stimulate the
development of more rational and effective approaches for
treating t(8;21) patients using histone deacetylase
inhibitors or HSP90 inhibitors.
A mini-review on the advances in other sub-types of AML
Inv(16)(p13q22) is associated with AML M4Eo, which is
characterized by the presence of myelomonocytic blasts and
atypical eosinophils. This chromosomal rearrangement
results in the fusion of CBFβ and
MYH11 genes. CBFbeta normally interacts with RUNX1 (AML1) to form a
transcriptionally active nuclear complex. Knockout of CBFbeta
causes embryonic lethality because of a lack of definitive
hematopoiesis. The MYH11 gene encodes the smooth
muscle myosin heavy chain (SMMHC). The CBFbeta-SMMHC fusion protein is capable of binding to RUNX1
and forms dimers and multimers through its myosin tail.
Results from transgenic mouse models show that
CBFβ-MYH11 is able to inhibit predominantly RUNX1 function
in hematopoiesis, and is a key player in the pathogenesis of
leukemia[107]. The myeloid transcription factor
CCAAT/enhancer-binding protein alpha (CEBPα) is crucial for
normal granulopoiesis. Alterations to the structure and
expression of CEBPα have been implicated in particular
subtypes of AML. Helbling et
al[108] found that conditional
expression of CBFβ-SMMHC in U937 cells suppressed
CEBPα protein expression and binding activity. However,
CEBPα mRNA levels remained unchanged. No differences
were detected in CEBPα mRNA levels in patients with
inv(16) AML M4Eo (n=12) compared to patients with AML with
a normal karyotype and M4 subtype (n=6), whereas
CEBPα protein and binding activity were significantly reduced in
patients with CBFβ-SMMHC. Furthermore, calreticulin, an
inhibitor of CEBPα translation, was induced on mRNA and
protein level in AML patients with CBFβ-SMMHC and after
expression of CBFβ-SMMHC in the U937-cell system.
Inhibition of calreticulin by siRNA restored CEBPα levels. These
results suggest that modulation of CEBPα by calreticulin
represents a novel mechanism involved in the
differentiation block in CBFβ-SMMHC AML. Recently, Wunderlich
et al[109] introduced the
CBFβ-MYH11 cDNA into human CD34+ cells via retroviral transduction. Transduced cells displayed
an initial repression of progenitor activity but eventually
dominated the culture, resulting in the proliferation of clonal
populations for up to 7 months. Long-term cultures
displayed a myelomonocytic morphology while retaining
multilineage progenitor activity and engraftment in
NOD/SCID-B2M-/- mice. Progenitor cells from long-term
cultures showed altered expression of genes defining inv(16)
identified in microarray studies of human patient samples.
This system will be useful in examining the effects of
CBFbeta-SMMHC on gene expression in the human
preleukemic cell, in characterizing the effect of this oncogene
on human stem cell biology, and in defining its
contribution to the development of leukemia.
The MLL-AF9 oncogene _ one of the most frequent
MLL/HRX/ALL-1 rearrangements found in infantile and
therapy-related leukaemias _ originates from
t(9;11)(p22;q23) and is mainly associated with monocytic AML (AML
M5). Pession et al[110] investigated the MLL-AF9 function
using an antisense
phosphorothioate-oligodeoxyribonucle-otide (MLL-AF9-PS-ODNas) and a THP-1 AML-M5 cell
line carrying t(9;11). Having confirmed that
MLL-AF9-PS-ODNas induced a strong inhibition of THP-1 cell growth
and a moderate increase in apoptosis, they found that
MLL-AF9-PS-ODNas did not induce morpho-functional
terminal differentiation or restore M-CSF-, G-CSF- or
GM-CSF-induced differentiation. Moreover, THP-1 cells showed
the same phenotype with/without MLL-AF9-PS-ODNas. In
THP-1 cells differentiated to mature macrophage-like cells
by PMA/TPA or ATRA, MLL-AF9 expression was down-regulated. Thus, in the monocytic lineage, MLL-AF9 may
be expressed only in early phases and can induce
deregulated amplification in both non-malignant and malignant cells,
maintaining the monocytic phenotype without blocking
final maturation. Barabe et
al[111] showed that after transplantation into immunodeficient mice, primitive human
hematopoietic cells expressing MLL-AF9 or MLL-ENL
generated myeloid or lymphoid acute leukemias, with features
that recapitulated the human diseases. An analysis of
serially transplanted mice revealed that the disease is sustained
by leukemia-initiating cells (L-IC) that have evolved over
time from a primitive cell type with a germline
immunoglobulin heavy chain (IgH) gene configuration to a cell type
containing rearranged IgH genes. The L-IC retained both
myeloid and lymphoid lineage potential and remained
responsive to microenvironmental cues. The properties of
these cells provide a biological basis for several clinical
hallmarks of MLL leukemias. By using a mouse model of human
AML induced by the MLL-AF9 oncogene, Somervaille
et al[112] demonstrated that colony-forming cells (CFC) in the
bone marrow and spleen of leukemic mice were also leukemia
stem cells (LSC). These self-renewing cells: (1) were frequent,
accounting for 25%_30% of myeloid lineage cells at
late-stage disease; (2) generated a phenotypic, morphological
and functional leukemia cell hierarchy; (3) expressed mature
myeloid lineage-specific antigens; and (4) exhibited altered
microenvironmental interactions by comparison with the
oncogene-immortalized CFC that initiated the disease.
Krivtsov et al[113] isolated LSC from leukemias initiated in
committed granulocyte macrophage progenitors through
introduction of the MLL-AF9 fusion protein. The LSC were
capable of transferring leukemia to secondary recipient mice
when only 4 cells were transferred, and possessed an
immunophenotype and global gene expression profile very
similar to that of normal granulocyte macrophage progenitors.
However, a subset of genes highly expressed in normal
hematopoietic stem cells was re-activated in LSC. Thus, LSC
can be generated from committed progenitors without
widespread reprogramming of gene expression, and a leukemia
self-renewal-associated signature is activated in the process.
These findings define progression from normal progenitor
to cancer stem cell and suggest that targeting a self-renewal
program expressed in an abnormal context may be possible.
The LSC responsible for sustaining, expanding and
regenerating MLL-AF9 AML are downstream myeloid lineage cells,
which have acquired an aberrant Hox-associated self-renewal
program as well as other biological features of
hematopoietic stem cells.
Interstitial loss of all or part of the long arm of
chromosome 5, or del(5q), is a frequent clonal chromosomal
abnormality in human myelodysplastic syndrome (MDS), a
preleukemic disorder, and AML, and is thought to
contribute to the pathogenesis of these diseases by deleting one or
more tumor-suppressor genes. Although a major commonly
deleted region (CDR) has been delineated on chromosome
band 5q31.1, attempts to identify tumor suppressors within
this band have been unsuccessful. Liu et
al[114] focused their analysis of gene expression on RNA from primitive
leukemia-initiating cells, which harbored 5q deletions, and
analyzed 12 genes within the CDR that were expressed by
normal hematopoietic stem cells. They found that the gene
encoding alpha-catenin (CTNNA1) was expressed at a much
lower level in leukemia-initiating stem cells from individuals
with AML or MDS with a 5q deletion than in individuals with
MDS or AML lacking a 5q deletion or in normal
hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia
line with deletion of the 5q31 region, showed that the
CTNNA1 promoter of the retained allele was suppressed by
both methylation and histone deacetylation. Restoration of
CTNNA1 expression in HL-60 cells resulted in reduced
proliferation and apoptotic cell death. Thus, loss of expression
of the alpha-catenin tumor suppressor in hematopoietic stem
cells may provide a growth advantage that contributes to
human MDS or AML with del(5q).
ALL
Chromosomal aberrations are a hallmark of ALL, but
alone fail to induce leukemia. To identify cooperating
oncogenic lesions, Mullighan et
al[115] carried out a genome-wide analysis of leukemic cells from 242 pediatric ALL
patients using high-resolution, single-nucleotide
polymorphism arrays and genomic DNA sequencing. Their
analyses revealed deletion, amplification, point mutation and
structural rearrangement in genes encoding principal
regulators of B lymphocyte development and differentiation in
40% of B-progenitor ALL cases. The PAX5 gene was the
most frequent target of somatic mutation, and was altered
in 31.7% of cases. The identified PAX5 mutations resulted
in reduced levels of PAX5 protein or the generation of
hypomorphic alleles. Deletions were also detected in TCF3
(also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and
IKZF3 (AIOLOS). These findings suggest that direct
disruption of pathways controlling B-cell development and
differentiation contributes to B-progenitor ALL pathogenesis.
Moreover, these data demonstrate the power of
high-resolution, genome-wide approaches in identifying new
molecular lesions in cancer.
The NOTCH signaling pathway is essential in T-cell
development and NOTCH1 mutations are frequently present in
T-cell acute lymphoblastic leukemia (T-ALL). To gain
insight into its clinical significance,
NOTCH1 mutation was investigated in 77 patients with
T-ALL[116]. Detection of NOTCH1 mutation was done using RT-PCR amplification
and direct sequencing and compared with the
clinical/biological data of the patients. Thirty-two mutations were
identified in 29 patients (with dual mutations in 3 cases),
involving not only the heterodimerization and proline/glutamic
acid/serine/threonine domains as previously reported, but
also the transcription activation and ankyrin repeat domains
revealed for the first time. These mutations were
significantly associated with elevated white blood cell counts at
diagnosis and independently linked to short survival time.
Interestingly, the statistically significant difference in
survival according to NOTCH1 mutations was only observed in
adult patients (>18 years) and not in pediatric patients
(£18 years), possibly because of the relatively good overall
response of childhood T-ALL to the current chemotherapy.
NOTCH1 mutations could coexist with
HOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of
NOTCH1 mutation on prognosis was potentiated by
HOX11L2 but was attenuated by HOX11. These data suggest that
NOTCH1 mutation is an important prognostic marker in T-ALL and its
predictive value could be even further increased if
coevalu-ated with other T-cell-related regulatory genes. Thus, the
NOTCH pathway acts in combination with oncogenic
transcriptional factors on T-ALL pathogenesis.
Optimal use of antileukemic agents together with the
stringent application of prognostic factors for risk-directed
therapy in clinical trials has resulted in a steady
improvement in the treatment outcome of
ALL[24]. The future of treatment for ALL resides in defining the molecular pathways
underlying the pathogenesis of this disease and in further
elucidating the pharmacogenetic factors of the host.
Improved understanding of the pathological features of the
disease could in turn lead to the identification of new drugs
or targets for specific treatments and may even suggest
strategies for disease prevention. Selective potential targeted
therapies for ALL are listed in Table 2.
Studies on chronic myelogenous leukemia
CML is a clonal myeloproliferative disorder
characterized by genomic instability leading to its inevitable clinical
evolution from an easily controlled chronic phase (CP) to
a terminal blastic phase. The molecular mechanisms
involved in blastic crisis remain largely unknown. Monoallelic
deletions of the P53 gene in Chinese patients with CML in
blastic crisis have been reported[118]. A few CP patients had
additional abnormalities while most patients with disease
progression [accelerated phase (AP) and blastic crisis (BC)]
showed extra numerical and/or structural chromosomal
aberrations[119,120].
STI571/Imatinib/Gleevec, a rationally designed agent
that occupies the ATP-binding site of BCR-ABL and
stabilizes the protein in its closed, inactive conformation, has
become the new gold standard for treatment of
CML[121_124]. However, its effects on patients with AP/BC are
unsatisfactory because many patients relapse after transient
remis-sion[125_127]. In addition, even among patients at CP, imatinib
seems unable to eradicate the malignant progenitors and a
significant portion of patients develop drug resistance after
long-term use. STI571-based combined protocols seem to
be feasible in the treatment of these patients. Yin
et al[128] investigated the combined effects of imatinib and
As4S4 on BCR-ABL and CML cells. They found synergic effects of
STI-571 and As4S4 in the treatment of K562 cells and fresh
CD34+ cells harvested from CML patients. Examination of
cell cycles showed that
As4S4 induced G2/M arrest, whereas
imatinib induced G1 arrest. Using a number of parameters,
such as morphology, annexin V/propidium iodide (PI),
mitochondrial transmembrane potential, caspase-3 activity and
Fas/Fas-L, the synergistic effects were revealed on
induction of cell apoptosis, largely through the mitochondrial
pathway. The 2 drugs also exhibited a synergistic effect in
targeting BCR-ABL protein. Although
As4S4 triggered its degradation and imatinib inhibited its tyrosine kinase activity,
combined use of the 2 drugs led to lower protein/enzymatic
activity levels of BCR-ABL. The in vitro data strongly
suggested a potential clinical application of imatinib and
As4S4 in combination on CML. To understand the mechanisms
underlying the synergistic action of these agents, Du
et al[129] applied cDNA microarrays, a component plane
presentation integrated self-organizing map (CPP-SOM), and
methods of protein biochemistry to study cell apoptosis induced
by imatinib mesylate, ATO and a combination of the 2 agents
in the CML cell line K562. Numerous features with
temporo-spatial relationships were revealed, indicating the
coordinated regulation of molecular networks from various aspects
of pro-apoptotic and apoptotic activities in CML. Imatinib
mesylate appears to mainly induce the intrinsic pathway of
cell apoptosis, whereas ATO induces the endoplasmic
reticulum (ER) stress-mediated pathway of cell apoptosis, and a
combination of the 2 agents seems to more effectively
induce the intrinsic, extrinsic and ER stress-mediated
pathways of cell apoptosis, which results in a more effective and
efficient induction of programmed cell death in K562 cells.
This finding also appears to be supported by data derived
from bone marrow cells of 2 patients with CML, 1 in chronic
phase and the other in blast-crisis phase of the disease.
Studies on chronic lymphoid leukemia
CLL is a clinically heterogeneous disease originating from
B lymphocytes that may differ in activation, maturation state
or cellular subgroup[130]. It is the most common form of
leukemia in developed countries and mainly affects elderly
individuals. CLL cells can avoid death by responding to
signal molecules or may undergo apoptosis, followed by
replacement from proliferating precursor cells. CLL is a
low-grade B-lineage lymphoid malignancy that follows an
extremely variable course, with survival ranging from months
to decades. Treatment decision is based on stage and
disease progression, with chemotherapy, purine analogs
(fludarabine, pentostatin and cladribine) and Rituximab (an
anti-CD20 mAb) as first-line
treatment[131].
The heritability of B-cell CLL is relatively high; however,
no predisposing mutation has been convincingly identified.
Raval et al[132] reported that loss or reduced expression of
death-associated protein kinase 1 (DAPK1) underlined cases
of heritable predisposition to CLL and the majority of
sporadic CLL. Epigenetic silencing of DAPK1
by promoter methylation occurred in almost all sporadic CLL cases.
Furthermore, these researchers defined a disease haplotype,
which segregated with the CLL phenotype in a large family.
DAPK1 expression of the CLL allele was downregulated by
75% in germline cells as a result of increased HOXB7 binding.
In the blood cells from affected family members, promoter
methylation resulted in the additional loss of
DAPK1 expression. Thus, reduced expression of
DAPK1 could result from germline predisposition, as well as epigenetic or
somatic events causing or contributing to the CLL
phenotype[132].
miRNA constitute a novel, phylogenetically extensive
family of small RNA (~22 nucleotides) with potential roles in
temporal and tissue-specific gene regulation. miRNA
alterations are involved in the initiation and progression of
human cancer. Calin et al[133] showed that miR15 and miR16
were located at chromosome 13q14, a region deleted in more
than half of B-CLL. Detailed deletion and expression
analysis showed that miR15 and miR16 were located within a
30-kb region of loss in CLL, and that both genes were
deleted or downregulated in the majority (~68%) of CLL cases.
Two years later Calin et al[134] reported genome-wide
expression profiling of miRNA in human B-CLL using a microarray
containing hundreds of human precursor and mature miRNA
oligonucleotide probes. This approach allowed them to
identify significant differences in miRNome expression between
CLL samples and normal CD5+ B cells; data were confirmed
by Northern blot analyses and real-time RT-PCR. At least
two distinct clusters of CLL samples could be identified that
were associated with the presence or absence of
Zap-70 expression, a predictor of early disease progression. Two
miRNA signatures were associated with the presence or
absence of mutations in the expressed Ig variable-region genes
or with deletions at 13q14, respectively. These data suggest
that miRNA expression patterns have relevance to the
biological and clinical behavior of CLL. In 2005,
Calin et al[135] investigated whether miRNA profiles were associated with
known prognostic factors in CLL. They evaluated the miRNA
expression profiles of 94 samples of CLL cells for which the
level of expression of ZAP-70, the mutational status of the
rearranged immunoglobulin heavy-chain variable-region
(IgVH) gene, and the time from diagnosis to initial treatment
were known. They also investigated the genomic sequence
of 42 miRNA genes to identify abnormalities. A unique miRNA
expression signature composed of 13 genes (of 190 analyzed)
differentiated cases of CLL with low levels of
ZAP-70
expression from those with high levels and cases with
unmutated IgVH from those with mutated
IgVH. The same miRNA signature was also associated with the presence or
absence of disease progression. A germ-line mutation in the
miR-16-1_miR-15a primary precursor was also investigated,
which caused low levels of miRNA expression in vitro
and in vivo and was associated with deletion of the normal allele.
Germ-line or somatic mutations were found in 5 of 42
sequenced miRNA in 11 of 75 patients with CLL, but no such
mutations were found in 160 subjects without cancer
(P<0.001). These data suggest that a unique miRNA signature
is associated with prognostic factors and disease
progression in CLL. Mutations in microRNA transcripts are
common and may have functional importance.
Conclusion and perspectives
The pathogenesis of leukemia involves an array of
molecular alterations that disrupt almost every facet of cell
transformation. A large variety of genetic alterations,
including point mutations, amplification, insertion, deletions,
trisomy and chromosomal translocations, are important in
leukemia initiation. Elucidation of genomic events and the
cascade of their effects in cell function is crucial for
identifying distinct subsets of leukemia and for developing new
therapeutic strategies[136]. Two paradigms come from the
identification of the key roles that PML-RARα and
BCR-ABL fusion proteins play in APL and CML leukemogenesis,
and from the development of ATRA/ATO and Imatinib, which
greatly improve the prognosis of patients with APL or CML,
respectively[137]. Optimal use of antileukemic agents has
also resulted in a steady improvement in the treatment
outcome of ALL[24]. Indeed, genomic medicine and the era of
molecular targeted leukemia therapy have clearly arrived,
and we should put the genome and targeted therapeutics
into the doctors' bag so that we can help patients to
conquer leukemia, a notorious enemy of mankind, especially
children.
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