12.the Impact of Trisomy 21 On Early Human Hematopoiesis

Editorials: Cell Cycle Features
Editorials: Cell Cycle Features
Cell Cycle 12:4, 533534; February 15, 2013; 2013 Landes Bioscience
The impact of trisomy 21 on early human

hematopoiesis
Anindita Roy,1 Gillian Cowan,1 Paresh Vyas2 and Irene Roberts1,*
2
1
Centre for Haematology; Imperial College London; London, UK;
MRC Molecular Haematology Unit; Weatherall Institute of Molecular Medicine; University of Oxford; Oxford,UK
Although children with Down syndrome

(DS) are not cancer-prone in general, they
have a 150-fold increased risk of acute
myeloid leukemia of DS (ML-DS) and a
33-fold increased risk of B-cell acute lymphoblastic leukemia (B-ALL).1 In virtually all cases of ML-DS, but not in other
leukemias, the leukemic cells acquire
N-terminal mutations in the GATA1 gene,
a key hematopoietic transcription factor and have an erythro-megakaryoblastic phenotype.2,3 The same N-terminal
GATA1 mutations are present in the clonally related, neonatal preleukemic disorder
transient abnormal myelopoiesis (TAM),
which is unique to DS and often precedes
ML-DS.2 The identification of GATA1
mutations in ML-DS and TAM, and
their unique association with DS and trisomy21 (T21) (GATA1 mutations are not
leukemogenic in the absence of T21), has
provided an exciting and potentially tractable model of human myeloid leukemogenesis and, more generally, the impact of
aneuploidy on human hematopoiesis.
T21 is likely to impact on hematopoietic cell biology in multiple complex ways.
Several genes on chromosome 21 (Hsa21),
such as RUNX1, ERG and DYRK1A,
encode proteins or microRNAs, such as
miR-125b, with relevant functions in
hematopoietic cells. However, while trisomic genes, individually or collectively,
may be directly involved through gene
dosage either in a hematopoietic cellautonomous fashion or via other cell types,
the effects may also be exerted indirectly
via disomic genes. To address this, several
investigators have studied mouse models
of DS.4 Although these models implicate
deregulated expression of Hsa21-encoded
genes as tumor-promoting, most evidence
suggests that the mouse may not be a suitable model.4 Critically, none of the models spontaneously develop TAM and/or
ML-DS. Furthermore, the hematopoietic phenotype of germline N-terminal
GATA1 mutations in disomic humans5 is
markedly different to mouse.
Adopting an alternative approach to
investigating the role of T 21 gene dosage,
we set out to determine the cellular consequences of T21 in primary human fetal
and neonatal hematopoietic cells, prior
to acquisition of GATA1 mutations. We,6
and others,7 found specific and marked
expansion of megakaryocyte-erythroid
progenitors (MEP) and proliferative
abnormalities of common myeloid progenitors (CMP) in DS fetal liver (FL) in
the absence of detectable GATA1 mutations. These observations have now been
supported by work in human T21 embryonic stem (ES) and induced pluripotent
stem (iPS) cells that illustrate arrested
erythroid-megakaryocyte progenitor/precursor differentiation both of embryonic8
and fetal stages of hematopoiesis.9
To investigate whether the abnormalities in T21 FL were confined to
MEP/CMP or extended to the hematopoietic stem cell (HSC) or multipotential progenitor (MPP) level, we recently
performed detailed immunophenotypic
and functional analysis of the HSC/MPP,
committed myeloid and B-lymphoid compartments of human T21 FL without
GATA1 mutations and compared these
with normal human FL.10 We demonstrated for the first time that in human FL,
T21 itself increases immunophenotypic
HSC, clonogenicity and MK-erythroid
output and biases erythroid-megakaryocyte primed gene expression with
associated MEP expansion. In addition,

immunohistochemical studies of T21
FL sections showed that megakaryocytes were both increased10 and abnormal (G. Cowan, unpublished data).
Furthermore, we found severe impairment of B-lymphoid development, with
~10-fold reduction in pre-pro B-cells and
B-cell potential of HSC, in tandem with
reduced HSC lymphoid gene expression
priming.10
These data support the notion that an
extra copy of Hsa21 in FL HSC is sufficient to perturb their growth and differentiation. This in turn would lead to an
increased FL MEP compartment and, following acquisition of GATA1 mutation(s),
to a selective expansion of a mutant
erythro-megakaryocytic leukemic blast
cell population manifesting as the clinical
condition TAM in late fetal, or early neonatal life (Fig. 1).
What our studies did not explain was
whether the perturbation of hematopoiesis in T21 FL was dependent on specific supportive interactions with the FL
microenvironment or, alternatively, was
entirely hematopoietic cell-autonomous.
Preliminary data show that while normal FL HSC reliably sustain multilineage bone marrow (BM) engraftment in
adult immunodeficient (NOD.Cg-Prkdcscid
Il2rgtm1Wjl /SzJ; NSG) mice, T21 FL HSC
engraft adult murine BM very poorly (G.
Cowan, unpublished data), implicating a
crucial role for the FL microenvironment.
On the other hand, where T21 FL cells
did engraft, the HSC/MEP expansion
and B-lymphoid deficiency of primary FL
cells was maintained. Together these data
support a model in which both cell-autonomous effects of T21 and the specialized
*Correspondence to: Irene Roberts; Email: [email protected]

Submitted: 12/14/12; Accepted: 01/09/13
http://dx.doi.org/10.4161/cc.23667
Comment on: Roy A, et al. Proc Natl Acad Sci USA 2012; 109:17579-84; PMID:23045701; http://dx.doi.org/10.1073/pnas.1211405109
www.landesbioscience.com
Cell Cycle
533
Importantly, B-lymphoid progenitors

were also reduced in T21 fetal BM compared with normal gestation-matched
controls (A. Roy, unpublished data) suggesting that molecular resetting of the
fetal B-lymphoid program may contribute
to B-cell immune deficiency and B-ALL
in children with DS.
In conclusion, recent data from primary human FL,10 as well as fetal BM,
ES cells and iPS,8,9 indicate that T21 itself
alters human fetal HSC and progenitor biology, causing multiple defects in
lympho-myelopoiesis. These data provide
clues to possible mechanisms through
which T21, or aneuploidy in general, may
perturb hematopoietic cell growth and
differentiation and a model with which to
investigate these. However, the molecular basis through which T21 exerts these
effects is likely to be extremely complex,
to be both tissue- and lineage-specific and
to be dependent on the FL, and possibly
fetal BM, microenvironment, analogous
to the role of the specialized tumor microenvironment in enabling and sustaining
neoplastic cancer cells.
References
Figure 1. Impact of trisomy 21 on fetal and post-natal hematopoiesis. Schematic representation of molecular, biologic and clinical data, summarizing the effect of trisomy 21 (T21) on fetal,
neonatal and childhood hematopoiesis. Fetal liver and, to a lesser extent, fetal bone marrow (BM)
trisomic for chromosome 21 demonstrate perturbed hematopoiesis with an expansion of the
hematopoietic stem cell compartment (HSC) and megakaryocyte-erythroid progenitors (MEP)
and reduced B lymphopoiesis, even in the absence of GATA1 mutations. Interaction of hematopoietic cells with the T21 fetal liver and/or BM microenvironment may play a crucial role in initiating
abnormal fetal hematopoiesis. Subsequent acquisition of GATA1 mutations in the abnormal/
expanded T21 fetal liver HSC and progenitors results in transient abnormal myelopoiesis (TAM) in
late fetal/neonatal life. Although most cases of TAM resolve spontaneously; in 1530% of cases,
additional genetic/epigenetic events lead to Down syndrome-associated acute myeloid leukemia
(ML-DS) before the age of 5 y. Abnormalities in hematopoiesis are likely to persist in childhood,
but detailed systematic studies are necessary to establish this.
fetal hematopoietic microenvironment

are necessary to drive abnormal hematopoiesis in DS. Consistent with this, we
have now found an increase in MEP and
534
clonogenic megakaryocyte progenitors in

T21 human fetal BM, although to a lesser
extent than in FL, and there is trilineage
perturbation of neonatal hematopoiesis.
Cell Cycle
1. Hasle H, et al. Lancet 2000; 355:165-9;

PMID:10675114; http://dx.doi.org/10.1016/S01406736(99)05264-2
2. Ahmed M, et al. Blood 2004; 103:2480-9;
PMID:14656875; http://dx.doi.org/10.1182/blood2003-10-3383
3. Wechsler J, et al. Nat Genet 2002; 32:148-52;
PMID:12172547; http://dx.doi.org/10.1038/ng955
4. Malinge S, et al. J Clin Invest 2012; 122:948-62;
PMID:22354171;
http://dx.doi.org/10.1172/
JCI60455
5. Hollanda LM, et al. Nat Genet 2006; 38:807-12;
PMID:16783379; http://dx.doi.org/10.1038/ng1825
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7. Chou ST, et al. Blood 2008; 112:4503-6;
8. Chou ST, et al. Proc Natl Acad Sci USA 2012;
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org/10.1073/pnas.1211175109
9. Maclean GA, et al. Proc Natl Acad Sci USA 2012;
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10. Roy A, et al. Proc Natl Acad Sci USA 2012; 109:1757984; PMID:23045701; http://dx.doi.org/10.1073/
pnas.1211405109
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Editorials: Cell Cycle Features

Editorials: Cell Cycle Features

The impact of trisomy 21 on early human

Although children with Down syndrome

associated MEP expansion. In addition,

*Correspondence to: Irene Roberts; Email: [email protected]

Importantly, B-lymphoid progenitors

fetal hematopoietic microenvironment

clonogenic megakaryocyte progenitors in

1. Hasle H, et al. Lancet 2000; 355:165-9;

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