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Micrornas Emerging key regulators of hematopoiesis.

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Critical Review
MicroRNAs: Emerging Key Regulators of Hematopoiesis
Violaine Havelange1 and Ramiro Garzon2*
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by pairing with their target
mRNAs, thereby inducing protein translation inhibition or/and mRNA degradation. There is now strong evidence that miRNAs play a crucial role in the regulation of hematopoiesis. Several groups have shown that
miRNA expression change dynamically during hematopoietic differentiation and functional studies demonstrated that miRNAs control not only differentiation but also activity of hematopoietic cells by targeting
transcription factors, growth factor receptors, and specific transcripts involved in the modulation of cellular
responses to external stimuli. In this review, we will summarize the current knowledge of miRNA expression
and function during hematopoiesis and discuss controversies and future directions. Am. J. Hematol.
C 2010 Wiley-Liss, Inc.
85:935–942, 2010. V
Introduction
Hematopoiesis is a highly regulated process controlled
by complex molecular events that simultaneously regulate
commitment, differentiation, proliferation, and apoptosis of
hematopoietic stem cells (HSC). Critical to this process is
a network of transcription factors which activation or inhibition is required to initiate the commitment of HSC to different lineages precursors [1]. Chromatin modifications
including histone acetylation and DNA methylation has
been recently recognized as regulatory mechanisms for
transcription factor expression regulation during hematopoiesis [2]. There is now strong evidence that a novel
class of noncoding RNAs, called microRNAs, modulate
hematopoietic differentiation, proliferation, and activity of
hematopoietic cells by targeting the expression of transcription factors and genes involved in the regulation of
cell cycling and proliferation.
MicroRNAs (miRNAs) are small (18-24 nucleotides) evolutionary conserved noncoding RNAs that bind to the
30 untranslated region (UTR) of target mRNAs resulting in
translation repression or mRNA degradation [3]. MiRNAs
are transcribed by polymerase II from unique miRNA
genes or from ‘‘host’’ genes (within intrones of known
protein-coding or noncoding genes) into initial precursor
of variable length called pri-miRNA [3]. This initial precursor is processed by the RNase Drosha to a 70- to 120nucleotides hairpin structure precursor called pre-miRNA
that is subsequently exported to the cytoplasm by exportin 5 [4]. Once in the cytoplasm, this pre-miRNA is further
processed by another RNAase; Dicer, resulting a 18- to
24-nucleotide duplex, that after losing the complementary
strand or passenger strand, is incorporated into the RNA
interfering silencing complex (RISC) [4]. The RISC is
comprised by Dicer, argonautes and Di George critical
region protein 8 proteins and is the effector pathway for
miRNAs canonical activity [3,4]. The mature miRNA
strand will direct the RISC complex to the target mRNA
based on the complementarity between the miRNA and
its target 30 UTR, resulting in mRNA cleavage when the
complementarity is perfect or in protein translation inhibition when the complementarity is imperfect [3,4]. A single
miRNA can control the levels of hundreds of different target genes and multiple miRNAs can regulate a single
mRNA [3,4]. Currently, there are 940 miRNAs registered
in Sanger miRNA registry (miRBase version 15). Strong
evidence indicates that miRNAs play important roles in
cellular processes such as proliferation, development, differentiation, and apoptosis [5–7]. Not surprisingly, we
and others have shown that miRNAs are dynamically
expressed during hematopoiesis and regulate differentiation and activity of hematopoietic cells (Fig. 1).
Chen et al. [5] firstly demonstrated that miRNAs are differentially expressed in mice hematopoietic tissues. The
authors found that miR-181 was expressed at high levels in
the murine thymus and differentiated B lymphocytes,
whereas it was detectable at lower levels in undifferentiated
progenitor cells. MiR-223 expression was confined to myeloid cells and miR-142 expression was highest in B-lymphoid tissues. Ectopic expression of miR-181 in hematopoietic
progenitor cells resulted in B lymphocyte proliferation upon
hematopoetic reconstitution. However, ectopic expression
of miR-142 or miR-223 did not induce any obvious phenotype [5].
Following this pioneer report, many groups have investigated the expression and function of miRNAs during hematopoiesis. In this review, we will describe miRNA expression
patterns during hematopoiesis and the functional implications of these expression changes. In addition, we will discuss controversies and future directions in the field. The
role of miRNAs in the initiation and progression of hematological malignancies has been extensively reviewed and will
not be discussed in this review [8–10].
MicroRNAs are required in hematopoiesis
Dicer is an RNase-III enzyme that is critical for miRNA
biogenesis. As expected, Dicer-deficient mice exhibit premature death at embryonic day 7.5 with a lack of detectable multipotent stem cells [11]. Conditional deletion of Dicer
in murine embryonic stem cells renders these cells unable
to differentiate [12]. Ablation of Dicer in early B-cell progenitors results in a developmental block at the pro- to pre-Bcell transition and the antibody repertoire is completely disturbed [13]. Within T cells, conditional Dicer deletion results
in impaired T-cell development and aberrant T helper cell
differentiation and cytokine production [14]. A severe block
in peripheral CD81 T cells in the thymus and a reduced
1
Hematological department, cliniques universitaires Saint-Luc, Université
catholique de Louvain, Brussels, Belgium; and 2Division of Hematology and
Oncology, Department of Internal Medicine, Comprehensive Cancer Center,
The Ohio State University, Columbus, Ohio
*Correspondence to: Ramiro Garzon, MD, The Ohio State University, Comprehensive Cancer Center, Biomedical Research Tower, Room 1084, 460
West 12th Avenue, Columbus, OH 43210.
E-mail: ramiro.garzon@osumc.edu
Received for publication 5 August 2010; Revised 17 August 2010; Accepted 18
August 2010
Am. J. Hematol. 85:935–942, 2010.
Published online 25 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.21863
C 2010 Wiley-Liss, Inc.
V
American Journal of Hematology
935
http://wileyonlinelibrary.com/cgi-bin/jhome/35105
critical review
Figure 1. Expression levels and regulatory networks of miRNAs during hematopoiesis. CLP, common lymphoid progenitor; CMP, common myeloid progenitor; DN, double negative T-cell precursors; DP, double positive (CD41CD81 T cells); EMP, erythrocyte-megakaryocyte precursor; EP, erythrocyte precursor; GMP, granulocyte-monocyte precursor; GP, granulocyte precursor; HSC, hematopoietic stem cells; MP, megakaryocyte precursor. Dashed green arrows means positive regulation; Red dashed
lines means negative regulation; Black Thick arrows follows hematopoiesis development and differentiation hierarchy; Small black arrows (up or down) means miRNA
expression during a specific hematopoietic stage. MiRNA targets or transcription factors involved in the regulation of miRNAs are shown using blue letters. [Color figure
can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
number of CD41 T cells are also observed; thereby indicating that miRNAs seems to be required for CD4/CD8 lineage commitment [15]. Altogether, data from germline and
conditional Dicer deletion indicate that miRNAs play a critical role in hematopoiesis.
MicroRNAs in HSC
Georgantas et al. [16] measured miRNA expression in
human CD341 selected HSC obtained from pooling mobilized peripheral blood stem cell harvests (PBSCH) or BM
samples from healthy donors. Using a microarray miRNA
platform, the authors identified 33 miRNAs expressed
(above background) in human CD341 cells from both peripheral blood HSC (PBHSC) and BM. These most abundant miRNAs in human BM CD341 cells were; miR-191,
miR-181, miR-223, miR-25, miR-26, miR-221, and miR222. The integration of in silico miRNA target predictions
with the microarray miRNA data, suggested that miRNAs
control hematopoietic differentiation through the translational control of mRNAs critical to hematopoiesis.
Liao et al. [17] isolated CD341 CD38- HSC and CD341
HSC from umbilical cord blood (UCB) and performed
miRNA microarray analysis. The miRNA expression profile
obtained from CD341 HSC was in high concordance with
the paper of Georgantas et al. [16]. The authors further
compared CD341 vs. CD341 CD38- HSC, arguing that
the latter subpopulation display stem cell properties compared to a more heterogenous and committed cell population identified only by positivity of CD34. The authors found
9 miRNA over-expressed and 22 down-regulated in CD341
CD38- HSCs compared with CD341CD381 cells. Among
the most up-regulated miRNAs in CD341 CD38- HSC,
miR-520h was predicted in silico to target ATP-binding cas-
936
sette, subfamily G (ABCG2), which is a gene involved in
stem cell maintenance. Transduction of miR-520h into
CD341 cells increased the numbers of multiple progenitor
colonies (CFU-E, BFU-E, and CFU-GM) and the number of
CD341 cells as well [17]. Therefore, the authors reasoned
that miR-520h may promote differentiation of HSC into
committed progenitors by inhibiting ABCG2 expression. It is
intriguing that higher miR-520h expression levels are
observed in CD341 CD38- HSC with respect to CD341
cells. One would expect that miR-520h will increase with
differentiation commitment. Further studies will be needed
to establish the role of miR-520h in hematopoiesis.
Using Taqman low density arrays, Merkerova et al., [18]
attained miRNA expression profiles of UCB CD341 cells.
There was high concordance in the miRNA expression of
UCB CD341 cells with respect to the other two previous
studies [16,17]. In this report, miR-520h was found highly
expressed in CD341 cells and deeply down-regulated in T
lymphocytes, monocytes, and granulocytes. Furthermore,
the authors found significant up-regulation of miRNAs that
were previously confirmed to target HOX genes, which are
involved in self-renewal of HSC/early progenitors. Consistent with previous reports indicating gene expression differences between UCB CD341 cells and BM CD341 cells
[19], likely due that UCB contains a larger population of
immature and pluripotent CD341 CD38- cells, the authors
found that the expression of 13 miRNAs was significantly
different between these cell types [18]. Interestingly, the
expression of the miRNA cluster comprised by miR-517c,
miR-518a, miR-519d, and miR-520h, was detected only in
UCB CD341 cells. By integrating transcriptome and miRNA
expression in these samples, the authors found negative
American Journal of Hematology
critical review
TABLE I. MicroRNAs with Important Role in Hematopoiesis
MiRNA
Erythropoiesis
miR-221 miR-222
Expression
Targets
Down
c-KIT
Up
FOXO3 GATA-2 Klfd
Bi-phasic
Down
Down
hALK4
PU-1/ETS-1 CEBPb/SHIP1
LMO2
Down
Down
Up
Down
MAFB
HOXA1
c-Myb
Ets-1/Meis1
miR-146a
Down
CXCR4
miR-125b-2
Myelopoiesis
miR-223
Down
DICER1/St18
Up G
NFI-A/E2F1 MEF2C
miR-21 miR-196a
Up G/GM
Unknown
miR-424
Up Mo
NFI-A
miR-17-92
Down Mo
AML1
Down prog.
c-Myb
miR-451 miR-144
miR-24
miR-155
miR-223
Megakaryopoiesis
miR-130a
miR-10a
miR-150
miR-155
Lymphopoiesis
miR-150
miR-181a
miR-17-92
miR-155
Up mature B/T cells
Up prog. and in
DP T cells Down
in mature B/T cells
Up in B/T precursors Down
in mature B/T cells
Up in Tregs and in
activated T/B cells
BCL2/CD69 TCR/DUSP5
DUSP6/SHP2 PTPN22
Bim PTEN
SOCS1 SHIP-1 CEBPb AID
Function
Inhibits early erythroid
proliferation Controls perinatal
HB switching
Regulates oxidative stress,
positive regulation of terminal
erythroid differentiation
and in zebrafish hemoglobin
synthesis (miR-144)
Modulates negatively erythropoiesis
Inhibits erythropoiesis
Inhibits erythropoiesis
Unknown
Unknown
Drives MK differentiation
Inhibits MK differentiation
and proliferation
Inhibits MK differentiation
and proliferation
Increase MK proliferation
Inhibits granulocytic proliferation
and activity
Regulation between
CMP-GMP transition
Induces Mo differentiation
and proliferation
Inhibits Monopoiesis in vitro but
no effects in vivo
Inhibits the transition from pro-B
to pre-B cells
Block DN3 to DN4 T-cell transition
Increases CD191 cells/Modulate
late thymic T-cell development,
TCR sensitivities and strenght
Modulates positively the transition
from pro-B to pre-B cells
Enhanced Tregs proliferation
Maintain competitive Treg
fitness Regulates GC-B cells
responses, innate imunity,
T-cell dependent antibody responses,
negative regulator of
somatic hypermutation
Regulated by
References
Unknown
20,23-25
GATA-1
23, 25-30
Unknown
AP-1, JNK
CEBPa, NF1A, E2F1
32
23,26, 34-35
33
Unknown
Unknown
Unknown
AP-1, JNK
37
37
38,40
12, 34-35, 44
PLZF
41
Unknown
43
CEBPa, NFI-A, E2F1
45-48
GFI-1
52
PU.1
53-54
AML1
55-56
Unknown
64-65
Unknown
67-68
c-Myc, E2F1
56,69
Foxp3
35, 73-78
MK, megakaryopoiesis; Mo, monopoiesis; GC, germinal center; DN3, double negative stage 3; DN4, double negative stage 4; CMP, common myeloid progenitors;
GMP, granulocyte-monocyte progenitors; Prog, progenitors; Tregs, T regulatory cells.
correlations among in silico predicted miR-520 targets (51
genes) and miR-520h expression. Although ABCG2 mRNA
expression was not correlated, ID1 and ID3 genes, both
involved in terminal hematopoietic differentiation, were
found to inversely correlate with miR-520h [18].
Erythropoiesis
Felli and colleagues firstly reported that two miRNAs (miR221 and miR-222) were down-regulated during in vitro differentiation of UCB CD341 cells to erythroid precursors (Table I and
Fig. 1) [20]. The authors further demonstrated that the downregulation of both miR-221 and miR-222 was necessary to promote early erythroid proliferation of UCB CD341 cells. Notably,
both miRNAs target the tyrosine kinase receptor c-KIT, which is
critical for early erythroblasts expansion [21]. The down-regulation of both miR-221 and miR-222, unblocks KIT expression
and allows erythroblast expansion [20]. Forced expression of
miR-221 and miR-222 in UCB CD341 HSC inhibits KIT protein
expression and erythroid growth. While critical for early erythropoiesis, KIT expression is silenced in late erythropoiesis by multiple mechanisms, including the transcription factor GATA-1
[21]. Recently, Gabbianelli et al., [22] demonstrated that human
perinatal hemoglobin switching is under control of the KIT receptor and partially by miR-221/-222. Over expression of both
miRNAs in UCB progenitors caused a decrease of erythroblast
proliferation and of fetal hemoglobin content.
American Journal of Hematology
A systematic descriptive analysis of miRNA expression in
erythrocyte precursors obtained from peripheral blood mononuclear cells and cultured in a three phase liquid system,
revealed a progressive down-regulation of miR-150, miR155, miR-221, and miR-222, up-regulation of miR-16 and
miR-451 at late stages of differentiation and a biphasic regulation of miR-339 and miR-378 (Table I and Fig. 1) [23].
Others groups investigated miRNA expression using leukemic cell lines that exhibit erythroid differentiation on stimulation with chemicals (e.g., hemin), such as the erythroleukemia
cell line K562 (blastic phase Chronic myeloid leukemia) [24]
or murine erythroleukemia line (MEL) ,which are blocked at
the pronormoblast stage of differentiation [25]. Although there
were similarities in miRNA expression profiles attained using
primary UCB samples with respect to the differentiated cell
lines (e.g., up-regulation of miR-451, miR-24, and miR-16 and
down-regulation of miR-221-222 and miR-155 during erythropoiesis), notable differences were observed probably due to
the inability of cell lines to fully differentiate into mature erythrocytes and their leukemic origins.
Among all erythroid miRNA profiling studies, miR-451 is
the most consistent and significantly upregulated miRNA
after erythroid differentiation [23,25–28] (Table I and Fig.
1). Furthermore, its expression is specific to erythroid tissues. MiR-451 is transcribed in cluster with miR-144 from
937
critical review
chromosome 17 by the transcription factor GATA-1 [27]. Ectopic transfection of miR-451 promotes erythroid differentiation and hemoglobin content of murine erythroleukemia
cells while the antagomir has opposite effects [25]. Using a
zebrafish mutant (meunier: mnr) that expresses GATA-1 but
not miR-144 and -451, Pase et al. [28] recently reported
that erythropoiesis was initiated but the maturation was retarded in this model. MiR-451 over-expression partially rescued erythroid maturation.
The in vivo effects of miR-451 were explored by two
groups using morpholino technology in zebrafish models.
Dore et al. elegantly described that zebrafish embryos
depleted of miR-451 but not miR-144 exhibited severe anemia, despite forming erythroid precursors [27]. Pase et al.
[28] subsequently reported that the depletion of miR-451
but not miR-144 resulted in delayed erythroid maturation.
However, the authors did not observe severe anemia as
previously reported [27]. A possible explanation was
recently provided by a recent review by Zhao et al., [29]
arguing that the use of 1-phenyl-2-thiourea (PTU) in Dore
et al. studies to improve visualization of internal embryo
structures, may have caused excessive PTU-induced anemia due to its oxidative effects. It has been preliminary
reported that the miR-144/451 locus ablation in mice
causes mild hemolytic anemia at baseline and increased
erythroid susceptibility to oxidative stress through the direct
targeting of the transcription factor FoxO3, which activates
numerous erythroid anti-oxidant genes [29]. Rasmussen
et al., recently reported that mice deficient for the miR-144/
451 cluster exhibits late erythroblast maturation defects,
resulting in erythroid hyperplasia, splenomegaly, and a mild
anemia. Again, it seems that the phenotype is mainly
driven by the loss of miR-451 expression, because mice
deficient for miR-451 has a phenotype indistinguishable
from the miR-451/144 mice [30]. The data also suggest an
importance for miR-451/144 in providing robustness to
erythropoiesis under situation of oxidative stress. In addition, to FOX03, GATA-2 is a bona fide target of miR-451, at
least in fish [27]. There is some evidence that miR-144
may be involved in the regulation of zebrafish hemoglobin
synthesis by direct targeting of the Kruppel-like transcription
factor (Klfd) that activates a-E1 gene transcription, a embryonic form of alpha globin. Klfd binds to the promoters of
a-globin and miR-144/451 to activate their transcription
constituting a negative feedback circuitry [31].
Among other miRNAs differentially expressed during
erythropoiesis, miR-24 which is highly expressed in CD341
HSC and down-regulated during erythropoiesis, modulates
negatively erythropoiesis [32]. These effects are mediated
by direct targeting of Activin type I receptor, which promotes erythropoiesis in cooperation with erythropoietin.
Like miR-24, miR-223 is down modulated in unilineage erythroid culture of UCB CD341 cells. Enforced expression of
miR-223 inhibits erythroid maturation of human erythroleukemia cells and UCB CD341 progenitors [33]. This effect
is partially mediated by targeting the LIM-only protein 2
(LMO2) by miR-223 [33]. LMO2 is a transcription factor
that along with GATA-1, SCL/TAL1 and LDB1 constitutes a
multiprotein complex that promotes erythropoiesis (Table I
and Fig. 1).
Many reports indicate that miR-155 is down-regulated
during erythropoiesis induction in primary cells or cell lines
[23,26]. Consistent with this data, a decreased numbers of
erythroid precursors and circulating red cells were observed
in transplanted animals with HSC over-expressing miR-155
[34]. In contrast, there was no obvious erythroid phenotype
changes observed in the miR-155 knock out mice (Table I
and Fig. 1) [35].
938
Last, Zhao et al. showed a negative autoregulative feedback loop between miR-15a and c-Myb, whereas c-Myb
binds to miR-15a promoter and regulates its expression. In
turn, miR-15a binds to the 30 UTR of c-Myb and blocks its
translation. The expression of c-Myb and miR-15a are
inversely correlated in CD341 cells undergoing erythroid
differentiation. Enforced expression of miR-15a in normal
marrow mononuclear cells blocked erythroid and myeloid
colony formation in vitro [36].
Megakaryopoiesis
Our group first reported miRNA expression profiles during
in vitro megakaryocytic differentiation of BM CD341 progenitors [37]. We identified 19 miRNAs down regulated during
megakaryocytic differentiation of CD341 progenitors, including miR-10a, -10b, -30c, -106, -126, -130a, -32, and -143
among others (Table I and Fig. 1). Three of them (miR-223,
miR-15a, and miR-16-1) exhibited a biphasic expression pattern; early down-regulation and late up-regulation, suggesting a stage-specific function. Many of the downregulated
miRNAs are predicted to target megakaryocytc specific
genes, suggesting that the loss of these miRNAs, unblocks
their targets resulting in megakaryocytic differentiation.
Indeed, we found that miR-130 targets MAFB, which induces
GPIIb in synergy with GATA1, SP1, and ETS-1 (Table I) [37].
Other groups have reported functional studies involving
individual miRNAs in megakaryocytic differentiation. Lu
et al. [38] showed that miR-150, which is moderately
expressed in megakaryocyte/erythrocyte precursors (MEP),
exhibits increased expression in cells undergoing megakaryocytic differentiation while it is down-regulated in cells differentiating to the erythroid lineage (Table I and Fig. 1).
Using gain- and loss-of-function experiments, the authors
demonstrated that miR-150 drives MEP differentiation
towards megakaryocytes at the expense of erythroid cells
in vitro and in vivo by targeting the transcription factor cMyb. Mice bearing lower c-Myb expression as a result from
targeted mutations, exhibits marked anemia and increased
thrombocytosis with respect to controls, suggesting that cMyb is a critical player in the cell fate decision between
megakaryocyte/erythrocyte differentiations. This report
challenges the dogma that miRNA are merely fine differentiation tuners or activity regulators. Although the data are
provocative, experiments using available germline miR-150
knock out models may be warranted to strongly establish
the role of miR-150 in MEP cell fate decisions. To this end,
the miR-150 knock out mice were reported to be viable, fertile and morphologically normal, exhibiting only B-cell and
Tcell alterations, as will be further described [39]. Supporting a role for miR-150 in megakaryocytic differentiation,
Barroga et al. [40] reported that thrompoietin (TPO), the
primary humoral regulator of platelet production, suppressed c-Myb expression by increasing miR-150 expression in megakaryocyte precursors and TPO-dependent cell
lines. Another miRNA, miR-34a has been shown to
represses c-Myb expression and cyclin dependent kinases
during megakaryopoiesis in leukemic cell lines and primary
CD341 progenitors treated with TPO [41]. However, the
down-regulation of c-Myb preceded the up-regulation of
miR-34, indicating other mechanisms involved in c-Myb
regulation during the early days of culture.
There has been a report implicating miR-146 in megakaryopoiesis. Labbaye et al. [42] found that miR-146a is suppressed during human megakaryopoiesis and that ectopic
expression of this miRNA suppresses megakaryocyte differentiation and proliferation during in vitro culture of CD341
cells. The authors found that miR-146 targets the chemokine receptor 4 (CXCR4), which integrity is indispensable
for megakaryopoiesis (Table I and Fig. 1) [42].
American Journal of Hematology
critical review
Enforced expression of miR-125b-2 in human CD341
cells increases the number and the size of CFU-MKs without blocking megakaryocytic differentiation, suggesting that
this miRNA is controlling proliferation of MEP [43]. MiR125b-2 seems to target ST18 (suppression of tumorigenicity 18) and Dicer (critical enzyme involved in miRNAs biogenesis). Indeed, the authors found a regulatory negative
feedback loop between Dicer and miR-125b-2. Production
of miR-125b by Dicer resulted in suppression of Dicer protein expression levels and, consequently, impaired overall
miRNA processing (Table I).
Finally, the oncogenic miR-155 is highly expressed in
CD341 cells, but it is sharply down-regulated during in vitro
UCB CD341 cells differentiation to megakaryocytes [44].
The enforced expression of miR-155 in human CD341
cells impaired the proliferation and differentiation of megakaryocytes in vitro and in vivo, likely through direct targeting
of the pro-megakaryocyte transcription factors ETS-1 and
Meis-1 (Table I and Fig. 1) [12].
Myelopoiesis
One of the first studies to suggest a role for miRNAs during myelopoiesis was reported by Fazi and colleagues. The
authors found that miR-223 expression was strongly
induced in acute promyelocytic leukemia (APL) cell lines by
retinoic acid (RA) [45]. On RA treatment, CEBPa (a master
myeloid transcription factor that promotes granulocyticmonocytic differentiation) binds to the miR-223 promoter,
displaces the negative granulopoietic transcription factor
NFIA, and activates miR-223 transcription. Ectopic expression of miR-223 in APL cell lines induces granulocytic differentiation, whereas the knockdown of miR-223 exhibited
opposite effects. High expression of miR-223 was further
confirmed in human peripheral blood granulocytes, whereas
its expression was down-modulated during monopoiesis
[45]. These data lead to the authors to reason that miR223 is a positive regulator of granulopoiesis. However, mice
deficient for miR-223 expression exhibit an increase in peripheral blood and bone marrow neutrophils [46]. The mutant neutrophils displayed unusual morphology, aberrant
pattern of lineage specific markers expression and
increased reactivity to activating stimuli, including evidence
of spontaneous inflammatory lung pathology. Furthermore,
the authors showed that MEF2c, a transcription factor that
promotes myeloid progenitor differentiation, is a bona fide
target of miR-223 and the phenotype of the miR-223 deficient mice was partially corrected when the MEF2c gene
was genetically ablated (Table I and Fig. 1).
A recent study using acute myeloid leukemia (AML) cell
lines reported that the CEBPa induced miR-223 targets the
cell cycle regulator E2F1, thereby blocking cell cycle progression and myeloid proliferation [47]. Interestingly, E2F1
binds to the miR-223 promoter suppressing its transcription. Thus, CEBPa-miR-223 and E2F1 comprise a negative
autoregulatory loop in AML [47]. The implication of this
finding in normal hematopoiesis is unknown. These results
also provide with a complementary explanation for the
increased numbers of granulocytes observed in the miR223 deficient mice, since these effects could also be
explained by shorter cell cycle and increase proliferation
due to higher levels of E2F1 in the miR-223 deficient mice
with respect to the wild type controls. In conclusion, miR223 decreases myeloid proliferation and dampens granulocytic activation. These data also highlight the importance of
performing studies using knock in or knock out animal models, representing better models for establishing definitive
functional roles of miRNAs during hematopoiesis.
Several groups have also systematically profiled the
expression of miRNAs during RA-induced granulocytic dif-
American Journal of Hematology
ferentiation of APL cells [48–50]. Our group found 10 upregulated miRNAs (let-7a-3, miR-16-1, 2223, 215a, 215b,
let-7c, let-7d, 2342, 107, and 2147), whereas miR-181b
was down regulated [48]. We further confirmed that the
RA-induced down-regulation of the oncogenes BCL-2 and
RAS is partially mediated by miR-15a/-16-1 and several let7 family members. The expression profiles obtained by our
group in NB4 cells treated with ATRA were validated independently by an independent group in primary APL samples [50].
The growth factor independence gene (GFI-1) encodes a
transcriptional repressor which is required for normal granulopoiesis [1,51]. Mice and humans deficient in GFI-1
expression exhibit an arrest in myeloid differentiation and
have increased granulocytic precursors [1,51]. Using cell
lines and GFI-1 deficient mice, Velu et al. [52] found that
GFI-1 binds to the promoter region of miR-21 and miR196b and suppress their transcription. GFI-1 up-regulation
in granulocyte-monocyte progenitors (GMPs) from wild-type
mice was associated with a dramatic reduction of both
miR-21 and miR-196b. These results were validated in
human leukemic cell lines models of granulocytic and
monocytic differentiation. Over-expression of miR-21 in Linmurine BM cells resulted in a significant increase of monocytic colonies, whereas the use of anatgomiR-21 had opposite effects [52]. Ectopic expression of miR-196b resulted in
a significant loss of granulocytic colonies. However, coexpression of both miR-21 and miR-196b completely blocks
G-CSF induced granulopoiesis and lead to the accumulation of cells that exhibited morphological and immunophenotyping features of immature granulocyte and monocyte
precursors. Thus, the data indicate that these two miRNAs
are critical players in the GFI-1 activity controlling the transition between GMPs to granulocyte precursors (Table I
and Fig. 1) [52].
In monocyte development, it was reported that the transcription factor PU.1 activates miR-424, which in turn induces monocytic/macrophage differentiation in AML cell lines
and human CD341 cells [53]. These effects are mediated
at least in part by activating specific genes important for
monocyte/macrophage differentiation such as M-CSF receptor, through the direct repression of the negative regulator of monopoiesis: NFIA. The up-regulation of miR-424
was confirmed by other group [54] using cell lines monocytic differentiation models (Table I and Fig. 1).
Fontana et al. [55] reported that the miR-17-5p, miR-20a,
and miR-106a cluster are down regulated during monocytic
differentiation and maturation of human CD341 cells. Consequentially, the transcription factor AML-1, which is a
direct target for the three miRNAs, is unblocked and upregulated, thereby promoting monocytic-macrophage maturation and differentiation, while suppressing further the transcription of these three miRNAs (Table I and Fig. 1). The
ectopic expression of the three miRNAs delays terminal differentiation of monocytes, whereas their inhibition accelerates differentiation. Notably, mouse monopoiesis occurring
in the absence of miR-17-92 cluster expression is normal
[56]. Whether this is due to differences between mouse
and human monopoiesis or this is inherent to the in vitro
models used by Fontana et al., further clarification is
needed. This is another example on how mouse models
contradict sharply to data obtained using cell lines or primary cells in vitro differentiation models.
As we discussed previously, miR-125b has an important
role in increasing proliferation and self-renewal of human
and mouse megakaryocytic progenitors and MEPs [43]. In
contrast, overexpression of miR-125b in human and mouse
HSC, results in increased proliferation of inmature granulocytes (Table I and Fig. 1). Bousquet et al. [57] reported a
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critical review
strong up-regulation of miR-125b in MDS and AML with
t(2;11)(p21;q23). In vitro experiments revealed that miR125b was able to interfere with primary human CD341 cell
differentiation, and also inhibited terminal (monocytic and
granulocytic) differentiation in HL60 and NB4 leukemic cell
lines. While these results may be relevant for leukemia, in
particular megakaryoblastic leukemia in the context of
Down syndrome and AML/MDS with t(2 ;11), the relevance
of these findings for normal hematopoiesis is unclear.
The role of miR-155 during normal human hematopoiesis
was established using knock out animal models. Notably,
there were no myeloid abnormalities detected in the mice
deficient for miR-155 expression [35]. Although miR-155 is
not required for normal hematopoiesis, it may need to be
repressed during this process. Supporting this hypothesis,
sustained miR-155 expression in murine HSC causes myeloproliferation with extramedullary hematopoiesis, splenomegaly and dysplastic changes [34]. There was also a
decreased in the erythroid and megakaryocyte colonies
[12]. Certainly, these findings are important for leukemogenesis, since aberrant expression of miR-155 has been
described in distinct subsets of AML [58,59].
Jurkin et al., [60] reported that miR-146 expression is
detected at low levels in monocytes and it was absent in
neutrophils. The authors further identified miR-146a as a
regulator of monocyte and dendritic cell (DC) activation but
not myeloid/DC subset differentiation. Ectopic miR-146a in
monocytes and intDCs interfered with TLR2 downstream
signaling and cytokine production, without affecting phenotypic DC maturation.
Lymphopoiesis
Over the past few years, several groups have reported
strong data supporting a critical role for subsets of miRNAs
in lymphoid cells development and immune function.
Numerous in depth reviews has been recently published
[61–63]. Here, we will highlight the most important miRNAs
involved in the modulation of this lineage (Fig. 1).
miR-150
MiR-150 is mainly expressed in lymphoid tissues, including lymph nodes and spleen. The expression is restricted
to mature T and B lymphocytes but not in their progenitors.
Two groups independently reported that ectopic expression
of miR-150 in murine HSC greatly impairs the formation of
mature B cells and inhibits the transition from pro-B to the
pre-B-cell stage partially by increasing apoptosis [64,65]. In
one study, a less pronounced block was apparent in the Tcell lineage, at the double-negative 3(DN3) to double-negative 4 (DN4) transition. Mice deficient for miR-150 expression were viable and fertile, but exhibited phenotype
changes restricted to the lymphoid tissues, consisting of
expansion of B1 cells in the spleen and in the peritoneal
cavity, higher levels of serum immunoglobulins and
enhanced T-cell dependent immune responses [64]. The
authors further showed that these changes were caused at
least in part by up-regulation of c-Myb, a confirmed miR150 target. C-Myb is an essential transcription factor for
early lymphoid development and its targeted loss in B cells
leads to a block in B-cell differentiation from pro-B to pre-Bcell stage, identical to the phenotype observed on ectopic
over-expression of miR-150 [66] (Fig. 1).
miR-181
MiR-181 is comprised of three clusters, miR-181a-1/miR181-b-1 located in chromosome 1, miR-181a-2/miR-181b-2
located in chromosome 9, and miR-181c/miR-181d on
chromosome 19. MiR-181a is expressed highly in the thymus and at lower levels in the lymph nodes and BM [5].
Specifically, miR-181a expression is high in the early B-cell
differentiation stages and decreases from the pro-B-cell to
940
the pre-B-cell stage. The ectopic expression of mir-181a in
murine HSC resulted in an increase in the percentage of
CD191 B cells and decrease of CD81 T cells without
affecting other hematopoietic lineages in hematopoetic
reconstitution assays in vivo [5].
Further studies are required to establish the role of miR181 in B-cell development. With respect to T cells, miR181a is dynamically up-regulated at the double positive
(CD41 CD81) stage of thymocyte development and correlated inversely with the expression of three predicted miR181 targets; BCL-2, CD69 and the T-cell receptor (TCR)
alpha, all of them involved in positive T-cell selection [67].
Further experiments confirmed that these proteins are
bona fide targets of miR-181. A different group confirmed
experimentally that the ectopic expression of miR-181a in
thymic progenitor cells can promote CD4 and CD8 doublepositive T-cell development, supporting a role for miR-181
in late T-cell thymic development [68]. In addition, to development functions, miR-181 also modulates TCR signaling
strength and sensitivities, thereby influencing T-cell sensitivity to antigens. These effects are mediated by down-regulated expression of several protein tyrosine phosphatases,
including SHP-2, PTPN22, DUSP5 and DUSP6 which in
turn results in activation of TCR signaling molecules Lck
and Erk [68] (Fig. 1).
miR-17-92 cluster
The miR-17-92 cluster, which comprises six miRNAs
(miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR92-1), is highly expressed in B and T precursor cells but its
expression decreases after maturation. Mice with targeted
deletion of miR-17-92 cluster die rapidly after birth. This
was likely due to severely hypoplastic lungs and ventricular
septal defects [56]. In hematopoiesis, the absence of this
cluster inhibits B-cell development at the pro-B to pre-B
transition by increasing the levels of the proapoptotic protein Bim, a miR-17-92 target [56]. These experiments suggest that the miR-17-92 cluster acts specifically during the
transition from pre-B to pro-B lymphocyte development,
enhancing the survival of the B cells at this stage by targeting Bim. Consistent with this data, mice with targeted overexpression of the miR-17-92 cluster in the lymphocyte compartment develop severe lymphoproliferative disorder and
autoimmunity [69]. These mice have decreased levels of
Bim but also of the pro-apoptotic PTEN, which is another
confirmed miR-17-92 target with critical functions in lymphopoiesis (Fig. 1).
Other miRNAs
It has been reported that miR-146a expression might be
involved in cell fate determination in mouse lymphocytes,
because its level is substantially increased in T helper 1
cells and decreased in T helper 2 cells relative to its
expression in naı̈ve T cell [67,70] (Fig. 1). In addition systematic profiling of miRNAs was also performed in naı̈ve,
memory and effector T cells, revealing that very few miRNAs are dynamically up-regulated on antigen specific T-cell
differentiation [71].
Immune function
miR-155. MiR-155 is processed from a primary transcript
called B-cell integration cluster encoded by a gene originally isolated near a common retroviral integration site in
avian leucosis virus-induced lymphomas [72]. Although
miR-155 is dispensable for lymphocyte development, it has
crucial roles in the modulation of T- and B-cell responses in
vivo. Mice deficient for B-cell integration cluster/miR-155
are viable, fertile, exhibits early lung inflammation, and
have a dampened innate immune response [35]. Impaired
B-cell responses were evidenced by significantly reduced
amount of immunoglobulin M (IgM) and switched antigen-
American Journal of Hematology
critical review
specific antibodies. Furthermore, miR-155 deficient mice
were less responsive to immunization [35]. Using both,
knock out and knock in animal models, Thai et al. [73]
showed that miR-155 plays a critical role in the formation
and activity of germinal centers in the lymph nodes and in
T-cell dependent antibody responses. T cells from miR-155
deficient mice failed to produce significant levels of interleukin-2 and interferon-g and there was a bias toward Th2 differentiation, suggesting that miR-155 promots T helper type
1 responses. Overall, these broad miR-155 immune effects
are mediated in part by controlling cytokine production.
However, other miR-155 targets are likely to be important,
such as the transcription factor PU.1, which regulates immunoglobulin switching or c-Maf (T-cell responses) [74]. A
recent study also indicates that miR-155 may be involved in
the regulation and function of T regulatory cells in concert
with the transcription factor FOXP3 [75,76].
Two recent articles reported that miR-155 negatively regulates somatic hypermutation and Class-switch recombination
of the immunoglobulin locus by targeting the activationinduced cytidine deaminase (AID) protein in B cells [77,78].
AID plays a critical role in the regulation of these processes,
assuring the generation of a diverse antibody repertoire. Disruption of the interaction between miR-155 and AID, resulted
in increased class switch recombination, defective affinity
maturation and genomic instability as evidenced by the association with Myc-related translocations [77,78]. This stunning
finding is in concordance with a previous report indicating
that AID was required for MYC translocations that occurred
in the context of IL6 transgene expression [79]. Although,
within this context miR-155 seems to protect from Mycrelated translocations, mice deficient for miR-155 do not exhibit any B-cell malignancy suggesting that this mechanism
by itself may not be sufficient to induce malignancy [35].
Innate immunity miRNAs
MiRNAs have also involved in the regulation of mechanisms that defend the host from infection by other organism, in a nonspecific manner (known as innate immunity
processes).
Critical to these processes is the recognition of bacteria,
viruses, and other pathogens by the Toll family of extracellular
receptors and the initiation of intracellular signaling events, in
particular NF-Kb activation that is ultimately critical to establish
a defensive response. Three miRNAs, miR-155, miR-146, and
miR-132, are dramatically up-regulated on treatment of monocytes with endotoxin lipopolysacharide (LPS) that mimics signaling by bacterial infection [80]. Interestingly, miR-146a and b
are NF-Kb induced miRNAs, that target TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1
(IRAK1) genes, both genes encoded for two key adapter molecules downstream of Toll-like and cytokine receptors [80]. This
constitute a negative feedback system whereby bacterial components induce NF-jB, resulting in up-regulation of the miR146 genes, which, on processing, down-regulate levels of
IRAK1 and TRAF6 proteins, reducing the activity of the pathway. This creates a negative feedback loop to limit TLR signaling after exposure to extracellular ligand.
The up-regulation of miR-155 in response to LPS may
play a critical role in inducing myeloproliferation following
infection. O’Connell et al. [34] found a strong but transient
induction of miR-155 in mouse bone marrow after injection
of LPS that associated with granulocyte-macrophage
expansion. Similar results were observed upon sustained
expression of miR-155 in murine HSC hematopoietic reconstitution models [34].
Conclusion
A wealth of reports establish that miRNAs are part of
complex regulatory networks involving transcriptional fac-
American Journal of Hematology
tors and cytokines that co-operate to govern the expression
of the genetic program underlying the differentiation, proliferation and activity of hematopoietic cells. Although most of
the studies were carried out analyzing a single miRNA or a
cluster, it is likely that miRNAs may cooperate with other
miRNAs in the regulation of these processes. To that end,
the contribution of each miRNA to a certain phenotype
would need to be systematically investigated by performing
loss or gain of function in vivo studies.
Notable, a single miRNAs can act on several hematopoietic lineages and exert completely different functions
stressing the notion that miRNA effects are dependent on
the cell context and the expression of the target genes
within that cell.
Over the next years, research should focus on developing loss or gain of function animal models to provide definitive information about miRNA functions during hematopoiesis. Studies based only on cell lines or in vitro cultures of
primary cells have proven to be inconsistent or insufficient
for obtaining definitive answers. However, it will be important to recognize that these discrepancies may have a biological meaning. There are numerous examples of therapeutic modification of miRNA in adult mice by administering
antagomirs, miRNAs mimics or via retroviral approaches
that elicits different effects than germline manipulation of
miRNA genes. These differences may be due to experimental artifacts such as off target effects, but they also
could be due to differences in how organisms handle miRNAs at different times in development, such as compensatory mechanisms. It may be important to elucidate and
understand such differences, because manipulating miRNAs in adult organisms is a potential therapeutic possibility.
The advent of high throughput small RNA sequencing
will allow the discovery of novel miRNAs and other non
coding RNAs expressed during hematopoiesis that will
require further functional characterization. The integration
of miRNA expression with other datasets, including whole
mRNA expression, genome-wide DNA sequencing, and
epigenome studies may uncover functional relationships
and improved overall the understanding of non coding
RNAs in the regulation of hematopoiesis.
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