Hiperdiploidia LLA

GENES, CHROMOSOMES & CANCER 48:637660 (2009)
High Hyperdiploid Childhood Acute

Lymphoblastic Leukemia
Kajsa Paulsson
*
and Bertil Johansson
*
Department of Clinical Genetics,Lund University Hospital, Lund, Sweden
High hyperdiploidy (5167 chromosomes) is the most common cytogenetic abnormality pattern in childhood B-cell precur-
sor acute lymphoblastic leukemia (ALL), occurring in 2530% of such cases. High hyperdiploid ALL is characterized cytoge-
netically by a nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18, and 21 and clinically by a favorable prognosis.
Despite the high frequency of this karyotypic subgroup, many questions remain regarding the epidemiology, etiology, pres-
ence of other genetic changes, the time and cell of origin, and the formation and pathogenetic consequences of high hyper-
diploidy. However, during the last few years, several studies have addressed some of these important issues, and these, as
well as previous reports on high hyperdiploid childhood ALL, are reviewed herein. V VC
2009 Wiley-Liss, Inc.
DELINEATION OF HIGH HYPERDIPLOID
CHILDHOOD ALL
The high hyperdiploid subgroup was identied
rst in the early 1980s, when Kaneko et al. (1981)
described a distinct difference between the
distribution of modal chromosome numbers
between adult and childhood acute lymphoblastic
leukemia (ALL), emphasizing that hyperdiploidy
with modes between 50 and 59 was only seen in
pediatric cases. Furthermore, the vast majority of
the children were below the age of 4, the white
blood cell (WBC) counts were generally low, and
the blasts were non-T and non-B, i.e., B-cell pre-
cursor in modern nomenclature. In addition, an
excellent response to chemotherapy, as well as
long remissions, was noted. Although we will
return to the prognostic impact of high hyperdi-
ploidy, it should be stressed that Fritz Lampert,
performing DNA measurements and chromosome
studies of childhood ALL, already in 1967 reported
that some of them were characterized by a hyper-
diploid DNA content corresponding to 5059 chro-
mosomes and that survival was particularly long in
such cases, suggesting that the high hyperdiploid
cells were particularly sensitive to chemotherapy
because of their increased DNA content (Lampert,
1967). It is surprising that these seminal and early
ndings rarely are referred to in publications focus-
ing on high hyperdiploid ALL, something hope-
fully rectied in the present review.
At about the same time as the report by Kaneko
et al. (1981), the Third International Workshop on
Chromosomes in Leukemia (1981a,b) also found
an association between high hyperdiploidy and
pediatric ALL. Shortly afterward, several corrobora-
tive studies appeared, using either karyotyping or
DNA content measurements to identify this sub-
group (Kaneko et al., 1982; Look et al., 1982; Wil-
liams et al., 1982; Heerema et al., 1985; Kowalczyk
et al., 1985; Smets et al., 1985). Thus, by the mid
1980s, it had become clear that high hyperdiploidy
is a characteristic subgroup of childhood ALL.
DEFINITION OF THE HIGH
HYPERDIPLOID SUBGROUP
Whereas the term hyperdiploidy is clearly
dened in the cytogenetic nomenclature as 4757
chromosomes (ISCN, 2005), there is no consensus
as regards which cases that should be included in
the high hyperdiploid subgroup of childhood B-
cell precursor ALL. The decision to dene this
subset as more than 50 chromosomes, something
that has become universally accepted, may seem
arbitrary. However, Williams et al. (1982) noted
that this was a natural division because of the
bimodal distribution of chromosome numbers
(Fig. 1) and the clear differences in treatment
response between the >50 and 4750 chromo-
some groups. The upper limit of high hyper-
diploidy, however, varies among different
studies. Originally, all cases with more than 50
Supported by: Swedish Childhood Cancer Foundation; Swedish
Cancer Society; Swedish Research Council.
*Correspondence to: Kajsa Paulsson, Department of Clinical
Genetics, University Hospital, SE-221 85, Lund, Sweden. E-mail:
kajsa.paulsson@med.lu.se or Bertil Johansson, Department of Clin-
ical Genetics, University Hospital, SE-221 85, Lund, Sweden.
E-mail: bertil.johansson@med.lu.se
Received 4 March 2009; Accepted 31 March 2009
DOI 10.1002/gcc.20671
Published online 4 May 2009 in
Wiley InterScience (www.interscience.wiley.com).
REVIEW ARTICLE
V VC
2009 Wiley-Liss, Inc.
chromosomes were included; thus, no distinction
was made between hyperdiploid, near-triploid,
and near-tetraploid ALL. Although some investi-
gators still adhere to that tradition, it has recently
become apparent that cases with chromosome
numbers in the tetraploid range are genetically
distinct, with the vast majority harboring the
t(12;21)(p13;q22) [ETV6/RUNX1 fusion] (Attarba-
schi et al., 2006; Raimondi et al., 2006). Near-tet-
raploid cases should hence not be part of the
high hyperdiploid group. Conversely, based on
the presence of specic trisomies and tetrasomies
(see below) as well as on the modal number dis-
tribution (Fig. 1), it is quite clear that most hypo-
triploid cases should be included. In practice, the
upper limit has been variably dened as 61 (For-
estier et al., 2008a), 65 (Moorman et al., 2003;
Sharathkumar et al., 2008), and 67 (Raimondi
et al., 1996; Heerema et al., 2007). In most
instances, no reasons are given for choosing a par-
ticular cutoff, but in a recent analysis of trisomies
and tetrasomies at different modal numbers,
Heerema et al. (2007) concluded that the chro-
mosomal patterns differed between cases with
5167 chromosomes and those with >67 chromo-
somes. Considering that this is, to the best of our
knowledge, the only delineation of high hyperdi-
ploidy based on a clear-cut difference between
two neighboring modal numbers (67 and 68), we
have chosen to use an upper limit of 67 chromo-
somes. Therefore, high hyperdiploidy is dened
as 5167 chromosomes in the present review.
EPIDEMIOLOGY
Frequency of High Hyperdiploidy in ALL
High hyperdiploidy is generally found in 25
30% of pediatric B-lineage ALL (Table 1). In
contrast, modal numbers of 5167 are much less
common in adult B-lineage ALL and are rarely
seen in T-cell ALL or Burkitt leukemia/lym-
phoma (Fig. 2). Thus, high hyperdiploidy is
strongly associated with childhood ALL.
Although the reported frequencies of high
hyperdiploid cases are quite similar in different
studies, it should be stressed that the patient
cohorts may differ, for several reasons. First, the
denition of high hyperdiploidy has varied. Sec-
ond, also the age range has differed; adolescents
above the age of 15 and/or infants have been
included in some studies, but not in others. Con-
sidering the typical age distribution of high
hyperdiploidy (Fig. 3) this may introduce a fre-
quency variation. Third, and perhaps most impor-
tant, cytogenetic analyses of high hyperdiploid
ALL are notoriously difcult, and there is ample
evidence that many cases go undetected if only
chromosome banding is used. Already during the
1980s, it was shown that ow cytometry analysis
could identify an aneuploid DNA index, compati-
ble with high hyperdiploidy, in cases with a nor-
mal karyotype (Look et al., 1982; Smets et al.,
1985). Subsequently, interphase FISH analyses
were shown to increase the detection rate of high
hyperdiploid cases quite substantially (Berger
et al., 1994; Martin et al., 1996; Kasprzyk and
Secker-Walker, 1997; Ritterbach et al., 1998;
Nordgren et al., 2002; Pere z-Vera et al., 2004).
TABLE 1. Frequency of High Hyperdiploidy in Larger Series
of Pediatric B-Lineage ALL
Origin Frequency
a
Reference
Austria 24% (71/299) Attarbaschi et al. (2004)
France 31% (104/334) Groupe Francais de
Cytogenetique
Hematologique (1993)
Germany 27% (173/650) Lampert et al. (1991)
Germany/Italy 17% (48/286) Borkhardt et al. (1997)
Japan 25% (47/191) Kobayashi et al. (1994)
Netherlands 38% (100/266) Smets et al. (1995)
Nordic
countries
25% (168/679) Forestier et al. (2008a)
UK 27% (183/680) Chessells et al. (1997)
UK 30% (303/1013) UK Childhood Cancer
Study Investigators
(2000)
USA 33% (41/125) Williams et al. (1982)
USA 30% (55/183) Rubnitz et al. (1997)
USA 24% (54/222) Borowitz et al. (1998)
USA 28% (332/1178) Heerema et al. (2000)
USA 28% (38/135) Sharathkumar
et al. (2008)
a
P < 0.001 (chi square).
Figure 1. Modal chromosome number distribution of 637 cytoge-
netically abnormal pediatric (<18 years) B-lineage ALL reported in
the literature (Mitelman et al., 2009). Only unselected cases are
included. Two incidence peaks are clearly seen, one corresponding to
near-diploid cases and one to high hyperdiploid cases.
638 PAULSSON AND JOHANSSON
Genes, Chromosomes & Cancer DOI 10.1002/gcc
Thus, such analyses have proved to be a valuable
adjunct to conventional cytogenetic studies, with
FISH having the additional advantage of provid-
ing information on which chromosomes that are
gained, in contrast to ow cytometry. Since
hidden high hyperdiploidy has been detected by
FISH in one third of cytogenetically normal
childhood ALL and in close to 60% in karyotypi-
cally failed cases (Harrison et al., 2005), inter-
phase FISH analyses should denitely be
undertaken in pediatric ALL with uninformative
cytogenetic results.
Frequency of High Hyperdiploidy in Relation to
Geographic or Ethnic Background
Among larger series of pediatric B-lineage ALL
from different countries, the frequencies of high
hyperdiploidy vary between 17% and 38% (Table
1). Although this variation is statistically signicant,
it should be emphasized that in the vast majority
of studies the prevalence is 2530%, strongly indi-
cating that there is no pronounced geographic fre-
quency heterogeneity. However, larger cytogenetic
studies have only been reported from rather afu-
ent countries; thus, whether the frequency of high
hyperdiploid ALL may be different in developing
countries is presently unknown.
As regards a possible impact of ethnic back-
ground, only a few studies, all from the US, have
specically addressed this topic. Pui et al.
(1988b) noted that high hyperdiploid ALL was
signicantly more common in white than in
nonwhite children and subsequently reported
that this type of ALL was underrepresented
among African-Americans (Raimondi et al., 1996;
Pui et al., 2003). Similarly, Pollock et al. (2000)
found a lower frequency of high hyperdiploid
ALL in African-Americans. On the other hand,
Bhatia et al. (2002) did not observe a signicant
frequency difference of the various ploidy levels
in different ethnic groups; however, the lowest
incidence of high hyperdiploidy was seen among
African-Americans. Thus, ethnicity may play a
role in the occurrence of high hyperdiploid ALL,
but whether this is due to genetic or environmen-
tal factorsnature versus nurtureremains
unknown.
Frequency of High Hyperdiploidy in
Relation to Age
As seen in Figure 3, high hyperdiploid ALL
displays a pronounced incidence peak at 24
Figure 2. Modal chromosome number distribution of (A) 143
adult (18 years) B-lineage ALL, (B) 571 T-ALL, and (C) 286 Burkitt
leukemias/lymphomas with cytogenetic abnormalities reported in the
literature (Mitelman et al., 2009). Only unselected cases are included.
As seen, the incidence of high hyperdiploid cases is very low in all
three disorders.
Figure 3. Age distribution of high hyperdiploid B-lineage ALL
reported in the literature (Mitelman et al., 2009).
HIGH HYPERDIPLOID CHILDHOOD ALL 639
years, being very rare in infant ALL and also
quite infrequent in patients above the age of 7;
the median age has been reported to be 3.63.9
years in larger studies (Table 2). In fact, high
hyperdiploid cases comprise the largest karyo-
typic subgroup of the frequency peak at 27
years of all childhood ALL. Together with ETV6/
RUNX1-positive cases, they constitute 50% of
all childhood ALL and almost 80% of ALL
occurring in the 27 years age peak (Forestier
and Schmiegelow, 2006).
Frequency of High Hyperdiploidy in Relation
to Gender
Retrieving all cytogenetically characterized B-
lineage ALL with modal chromosome numbers
between 51 and 67 in children/adolescents below
the age of 18 reported in the literature (Mitelman
et al., 2009) reveals a male/female ratio of 1.3.
That high hyperdiploidy may be more common
in boys has also been reported in some previous
studies; however, the sex ratio is close to 1.0 in
all larger series (Table 2). Thus, if there is really
a male preponderance, it is not particularly
pronounced.
ETIOLOGY
Although there is a seemingly never-ending list
of possible risk factors for childhood ALL,
including parental, in utero, and postnatal expo-
sures as well as genetic susceptibility, it seems
safe to conclude that many are called, but few
are chosen. Furthermore, and unfortunately,
most studies addressing this important issue treat
ALL as a single entity, not taking into account
the diverse clinical, phenotypic, and genetic fea-
tures that characterize this heterogeneous dis-
easeas succinctly stated by Greaves (1997):
different biological subtypes of leukaemia may
have distinct causal mechanisms.
Considering that high hyperdiploidy is the
most common cytogenetic abnormality pattern in
pediatric ALL, surprisingly little is known about
its etiology. As discussed below, several studies
have provided circumstantial evidence that this
karyotypic feature arises in a single mitosis al-
ready before birth. This suggests that exposure to
transforming agents during pregnancy, probably
in cooperation with genetic risk factors, is impor-
tant and that postnatal second hits, which also
may be caused by environmental agents and
modulated by constitutional factors, are necessary
for overt leukemia. Thus, to further our under-
standing of the etiology of high hyperdiploid
ALL both genetic risk factors as well as prenatal
and postnatal exposures warrant investigation.
Genetic Risk Factors
Down syndrome (DS) has long been known
to be associated with an 20 fold increased risk
of ALL (Krivit and Good, 1957; Hasle, 2001).
The proportion of high hyperdiploid DS-ALL
has been shown to be signicantly lower
(10%) than in non-DS-ALL patients (25
30%). This notwithstanding, it is clear that a
constitutional trisomy 21 still increases the risk
for high hyperdiploid ALL (Forestier et al.,
2008b). High hyperdiploid DS-ALL are charac-
terized by gains of the same chromosomes as
non-DS ALL, strongly suggesting the same eti-
ology and/or pathogenesis of high hyperdiploidy
in children with or without DS (Forestier et al.,
2008b). No other constitutional chromosome ab-
normality has been correlated with high hyper-
diploid ALL.
Despite the fact that several Mendelian disor-
ders have been associated with acute leukemia
(Online Mendelian Inheritance in Man, 2009),
they do not seem to increase the risk for high
hyperdiploid ALL; there are, as yet, no known
highly penetrant recessive or dominant genes
linked to the development of this ALL subtype.
Attention has instead been focused on suscepti-
bility due to low penetrance genes. However,
analyses of genetic polymorphisms as a risk fac-
tor for high hyperdiploid ALL have thus far
been quite unsuccessful. Chen et al. (1997)
identied glutathione S-transferase deletions as
a risk factor, but those with this genotype more
often had non-high hyperdiploid ALL. On the
other hand, the HLA-DPB1*0201 allele, belong-
ing to the HLA class II genes that are important
in adaptive immune responses to infection, has
been shown to be signicantly more common in
children with hyperdiploid ALL than in healthy
infants, suggesting that it increases the risk for
this type of ALL (Taylor et al., 2002). Hence,
there may be genetic risk factors for high hyper-
diploid ALL, but based on available evidence,
in particular that siblingstwins excludedto
children with ALL do not have an increased
risk of ALL (Schmiegelow and Hjalgrim, 2006),
constitutional genetics does not seem to be a
major etiologic factor.
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Environmental Risk Factors
No parental exposure has been specically
associated with an increased risk of having a child
developing high hyperdiploid ALL. However, it
has been suggested that maternal and/or paternal
exposure to organic solvents or use of mind-
altering drugs, such as amphetamine, marijuana,
and cocaine, correlates with the presence of RAS
mutations in pediatric ALL (Shu et al., 2004).
Considering that RAS mutations have been
shown to be relatively common in high hyperdi-
ploid ALL (Wiemels et al., 2005; Paulsson et al.,
2008b), this may indirectly suggest that use of
such drugs may increase the risk for high hyper-
diploidy. On the other hand, Wiemels et al.
(2005) reported that high hyperdiploid ALL is
signicantly less common in children prenatally
exposed to paternal smoking, speculating that
smoking-associated mutagens may be toxic to the
hyperdiploid clone. Although one could thus
argue that a reasonable advice to parents-to-be, in
order to decrease their risk of having a child
developing high hyperdiploid ALL, would be to
stop using mind-altering drugs and to start smok-
ing, we would like to stress that further studies
are needed to conrm or refute these very pre-
liminary associations.
Turning from drugs to vitamins, an increased
risk for childhood ALL, albeit not specically
for the high hyperdiploid subtype, has been
associated with low folate intake during preg-
nancy (Thompson et al., 2001), although this
was not conrmed in a subsequent study (Dock-
erty et al., 2007). Interestingly, folate deciency
has been shown to induce aneuploidy of chro-
mosomes 17 and 21 in cultured lymphocytes,
suggesting a possible association between dis-
turbances in this metabolic pathway and hyper-
diploidy (Wang et al., 2004). Wiemels et al.
(2001) found that constitutional homozygosity
for certain polymorphisms in the MTHFR gene,
coding for the enzyme methylenetetrahydrofo-
late reductase involved in the folate metabolic
pathway, is less common in hyperdiploid cases.
In fact, these MTHFR alleles have been associ-
ated with a reduced risk of pediatric ALL in
general (Krajinovic et al., 2004). Further support
for involvement of folic acid metabolism comes
from the study by Gast et al. (2007) who
showed that different haplotypes of the MTRR
gene, also involved in this pathway, correlate
with increased or decreased risk of childhood
ALL. Unfortunately, they did not analyze dif-
ferent cytogenetic subgroups separately.
It has been hypothesized, based on data on
population mixing, international incidence-rate
comparisons, time trends, and socioeconomic sta-
tus, that pediatric B-lineage ALL occurring in the
childhood peak arises as a consequence of a rare,
abnormal response to a common infection
(Greaves, 1988; Kinlen, 1988). Support for this
hypothesis has emerged from case-control studies
showing that daycare attendance, used as a proxy
for early infections, is associated with a reduced
risk of ALL (Greaves, 2006). However, this has
not, as far as we know, been specically linked to
the high hyperdiploid subgroup.
After a meta-analysis of several epidemiological
studies, Hjalgrim et al. (2003) concluded that
children weighing more than 4 kg at birth were
at increased risk of developing acute leukemia, in
particular ALL. In a later population-based case-
control study, the same group not only conrmed
this association but also showed that birth weight
was a risk factor for high hyperdiploid as well as
for t(12;21)-positive ALL (Hjalgrim et al., 2004).
The underlying mechanisms are unknown, but
could involve levels of insulin-like growth factor
1 and/or increased bone marrow volume, the lat-
ter yielding more cells vulnerable to leukemic
transformation (Hjalgrim et al., 2004).
CLINICAL CHARACTERISTICS
Peripheral Blood Values
High hyperdiploid ALL is generally associated
with low WBC counts; the median is <10 10
9
/l
in most series (Table 2). In cases from our own
department, the median is 5.9 10
9
/l (range,
1.3129), with 35% of cases having >10 10
9
/l
and 10% having >50 10
9
/l (unpublished data).
Thus, based on WBC counts quite few patients
would be stratied into high risk protocols. Data
on peripheral blast percentages are scarce, but
have been reported to be 3060% (Table 2);
these rather low frequencies should denitely be
taken into consideration when performing, for
example, array-based analyses of DNA extracted
from peripheral blood.
The patients are generally moderately anemic
at the time of diagnosis, with the median hemo-
globin levels generally varying between 60 and
75 g/l (Table 2). Most patients are also thrombo-
cytopenic, usually having median levels <50
10
9
/l. In our own data set, the median level is
42 10
9
/l (range, 5432), but it should be noted
that 15% of the patients have normal platelet
levels (unpublished data).
Extramedullary Leukemia
Extramedullary leukemia in the form of media-
stinal mass or central nervous system (CNS)
involvement, at the time of diagnosis is rare in
patients with high hyperdiploid ALL; as seen in
Table 2, the frequencies are less than 5%. Thus,
extramedullary leukemia is not a signicant factor
in this patient cohort.
Bone Marrow Morphology
In most instances, high hyperdiploid cases dis-
play a very high bone marrow blast percentage,
with the median being 95100% (Table 2). How-
ever, Knulst et al. (1993) reported a few patients
who presented with a smoldering high hyperdi-
ploid ALL where acute leukemia could not be
established by conventional morphological analy-
sis, i.e., the blast frequency was too low. The
prevalence of this phenomenon within the high
hyperdiploid group is unknown, but we are aware
of one such case at our department during the
last few years.
Several early studies showed that high hyperdi-
ploid ALL more often are of the FAB type L1
than L2, i.e., the cells are usually small and uni-
form and more rarely large and varied; they are in
all practice never L3 (Third International Work-
shop on Chromosomes in Leukemia, 1981b;
Williams et al., 1982; Heerema et al., 1985; Pui
et al., 1989; Secker-Walker et al., 1989; Kaspers
et al., 1995; Smets et al., 1995). However, there
are no characteristic morphological features that
can be used to deduce the presence of high
hyperdiploidy.
Immunophenotypic Features
Already in the initial report delineating high
hyperdiploid pediatric ALL, Kaneko et al. (1981)
noted that all cases had non-T-cell and non-
mature-B-cell markers, i.e., they belonged to the
group that today would be denoted B-cell precur-
sor. Subsequent studies during the 1980s showed
that the high hyperdiploid cases were character-
ized by the expression of the common (CD10)
ALL antigen (Third International Workshop on
Chromosomes in Leukemia, 1981a,b; Kaneko
et al., 1982; Williams et al., 1982; Heerema et al.,
1985; Smets et al., 1985; Harbott et al., 1987;
Heinonen et al., 1988; Michael et al., 1988; Pui
et al., 1988b; Fenaux et al., 1989; Secker-Walker
et al., 1989; Uckun et al., 1989). As more surface
markers were identied and used in immunophe-
notypic analyses, it gradually became apparent
that high hyperdiploid lymphoblasts typically are
positive for TdT, HLA-DR, CD10, CD19,
CD22, CD24, CD34, and CD66c and negative
for CD13, CD33, CD45, CD65, cIg, and sIg (Bor-
owitz et al., 1990; Behm et al., 1992; Groupe
Francais de Cytoge ne tique He matologique, 1993;
Lavabre-Bertrand et al., 1994; Raimondi et al.,
1996; Hrusa k et al., 1998; Hru sa k and Porwit-
MacDonald, 2002). However, in contrast to some
genetic subtypes, the immunophenotype cannot
be used to predict high hyperdiploidy.
OUTCOME
Lampert (1967) investigated 10 children with
ALL and noted that the four patients with 5059
chromosomes responded very well to induction
therapy and that their survival was particularly
long. Further support for a favorable outcome of
hyperdiploid ALL in general (>46 chromosomes)
was supplied a decade later by Secker-Walker
et al. (1978, 1979), who reported that such
patients had signicantly longer rst remissions
and better survival than those with diploid or
hypodiploid modal numbers. Subsequently,
Kaneko et al. (1981) described six children who
all achieved complete remission (CR) after induc-
tion treatment comprised only of vincristine and
prednisolone and who remained in CR for several
years. During the following years, numerous stud-
ies conrmed the favorable outcome of this cyto-
genetic subgroup (Kaneko et al., 1982; Williams
et al., 1982; Harbott et al., 1987; Heinonen et al.,
1988; Michael et al., 1988; Prigogina et al., 1988;
Bloomeld et al., 1989; Fenaux et al., 1989;
Secker-Walker et al., 1989), and by the end of
the 1980s, the favorable prognosis of high hyper-
diploid ALL had become widely recognized.
Event-Free and Overall Survival
As seen in Table 3, complete morphological
remission is achieved in the vast majority of high
hyperdiploid cases, i.e., initial treatment failure is
very rare. It is clear that this karyotypic feature is
associated with quite favorable event-free survival
(EFS) rates, often above 80% (Table 3). How-
ever, more dismal frequencies have been
reported, such as 73% at 5 years (Moorman et al.,
2003), and although late relapses are rare, they
have been noted to occur several years after ces-
sation of treatment (Dastugue et al., 1992). Very
recently, bone marrow brosis at diagnosis has
been associated with an increased risk of relapses
in the high hyperdiploid subgroup (Nore n-
Nystro m et al., 2008). The relapses most com-
monly involve the bone marrow (7080%), with
extramedullary involvement, mainly of the CNS,
occurring in a minority of cases (Pui et al., 1989;
Raimondi et al., 1996). However, it should be
noted that a trend toward an overrepresentation
of extramedullary relapses in this subgroup has
been reported (Sharathkumar et al., 2008).
Today, the overall survival (OS) rate of chil-
dren with high hyperdiploid ALL is 90% (Ta-
ble 3). Considering that the OS frequencies are
notably higher than the corresponding EFS rates
(Table 3), it is apparent that the treatment of
relapses generally is successful.
Possible Explanations for the Favorable Outcome
It has long been known that high hyperdiploid
ALL is particularly sensitive to chemotherapy,
especially to corticosteroids, mercaptopurine,
thioguanine, cytarabine, L-asparaginase (ASP),
and methotrexate (MTX) (Smets et al., 1987;
Synold et al., 1994; Kaspers et al., 1995). As
regards ASP, it has been shown that high hyper-
diploid blasts often display low expression of the
gene encoding asparaginase synthetase, some-
thing that may well explain the benecial effects
of asparagine depletion (Iwamoto et al., 2007).
The sensitivity to MTX is due to the increased
accumulation of MTX polyglutamates in the high
hyperdiploid blast cells (Whitehead et al., 1992,
1998; Synold et al., 1994). Intriguingly, the
SLC19A1 gene, which codes for the reduced fo-
late carrier that transports MTX into the cell, is
located at chromosome 21, which is trisomic or
tetrasomic in virtually all high hyperdiploid ALL.
Thus, the increased MTX accumulation may be
ascribed to additional copies of SLC19A1. In fact,
gain of chromosome 21 has been shown to be
associated with up-regulation of this gene in sev-
eral studies (Zhang et al., 1998; Belkov et al.,
1999; Cheng et al., 2005).
The successful response to chemotherapy is
most likely also linked to the activation of apo-
ptotic pathways in high hyperdiploid cells that
are already poised to die (Kersey, 1997).
Indeed, hyperdiploid blasts have been reported
to have quite a marked propensity to undergo
spontaneous apoptosis, both in vitro in stromal
TABLE 3. Outcome of Children with High Hyperdiploid B-Lineage ALL
Reference No. of cases CR (%) EFS (%) OS (%)
Kaneko et al. (1981) 6 100 NR NR
Kaneko et al. (1982) 9 100 NR NR
Williams et al. (1982) 41 95 NR NR
Heerema et al. (1985) 15 87 NR NR
Heinonen et al. (1988) 20 100 NR NR
Michael et al. (1988) 31 100 NR NR
Prigogina et al. (1988) 26 89 NR 40 (5 yr)
Bloomeld et al. (1989) 22 95 NR NR
Fenaux et al. (1989) 13 100 NR NR
Fletcher et al. (1989) 35 NR 80 (5 yr) 88 (5 yr)
Secker-Walker et al. (1989) 17 100 75 (5 yr) NR
Jackson et al. (1990) 146 100 75 (5 yr) NR
Hayashi et al. (1991) 13 100 NR NR
Rubin et al. (1991) 29 NR 93 (4 yr) NR
GFCH
a
(1993) 110 NR 85 (4 yr) NR
Kobayashi et al. (1994) 47 NR 74 (4 yr) NR
Raimondi et al. (1996) 105/63
b
NR 72/86 (5 yr) NR
Chessells et al. (1997) 195 NR 71 (5 yr) NR
Rubnitz et al. (1997) 55 NR 81 (5 yr) NR
Heerema et al. (2000) 480 NR 79 (8 yr) NR
Moorman et al. (2003) 807 NR 73 (5 yr) 91 (5 yr)
Moghrabi et al. (2007) 82 NR 86 (5 yr) NR
Forestier et al. (2008a) 168 NR 81 (10 yr) 89 (10 yr)
Sharathkumar et al. (2008) 38 NR 71 (5 yr) 93 (5 yr)
CR, complete remission; EFS, event-free survival; NR, not reported; OS, overall survival.
a
Groupe Francais de Cytogenetique Hematologique.
b
Cases with 5155 and 5667 chromosomes, respectively.
cultures and in vivo in bone marrow (Kumagai
et al., 1996; Ito et al., 1999; Zhang et al., 2002).
This may to some extent be explained by the rel-
atively high expression of the proapoptotic CAS-
P8AP2 gene at 6q15 in high hyperdiploid ALL
(Flotho et al., 2006).
Cytogenetic Features Inuencing the Outcome
Several studies have suggested that certain kar-
yotypic patterns and aberrations have a major
prognostic impact within the high hyperdiploid
subgroup, including modal numbers, specic tris-
omies, and structural changes.
Some investigators have reported a superior
outcome for cases with higher (>53 or >55)
modal chromosome numbers (Raimondi et al.,
1996; Heerema et al., 2000; Moorman et al.,
2003). However, Moorman et al. (2003) con-
cluded that this effect may simply be due to the
fact that such ALL are more likely to harbor 4,
10, and 18.
That certain trisomies might be associated with
prognosis was initially proposed by Jackson et al.
(1990), who correlated the presence of 6 with
improved EFS; however, their investigation also
included cases with 4750 chromosomes and was
hence not restricted to the high hyperdiploid sub-
group. Furthermore, an association between gain
of chromosome 6 and outcome has not been con-
rmed in subsequent studies. Harris et al. (1992)
reported increased EFS for high hyperdiploid
cases with both 4 and 10 compared with those
with trisomy of only one or none of these chro-
mosomes. However, Raimondi et al. (1996) could
not conrm that 4 and 10 inuence the prog-
nosis. Heerema et al. (2000) concluded that
whereas 4 and 6 did not affect the prognosis,
concurrent 10 and 17 were associated with a
superior outcome and 5 with a poor prognosis.
On the other hand, Moorman et al. (2003) found
an association between improved outcome and
trisomies 4, 10, and 18, but with only 4 and
18 having an independent impact in multivari-
ate analysis. Although these results seem conict-
ing, most studies have detected specic effects of
trisomies 4, 10, 17, and 18 in univariate analyses,
while the conclusions drawn from the multivari-
ate analyses have differed (Moorman et al., 2003).
In a study of >5000 pediatric B-cell precursor
ALL, Sutcliffe et al. (2005) showed that simulta-
neous trisomies 4, 10, and 17 were associated
with a very favorable outcome. Such triple triso-
mies are now used to stratify ALL as low stand-
ard risk in the US (Schultz et al., 2007).
However, to the best of our knowledge, specic
trisomies are not risk stratifying in European
treatment protocols.
A small subset of high hyperdiploid ALL har-
bors both near-haploid and high hyperdiploid
clones, with the latter representing a doubling of
the former (see below). It should be stressed that
such cases share the dismal outcome of near-hap-
loid ALL in general and that they should hence
be distinguished from the classic high hyperdi-
ploid cases (Harrison and Johansson, 2009).
As regards structural chromosome changes in
high hyperdiploid ALL, Pui et al. (1989) reported
that the presence of such aberrations in general
was associated with an increased risk of treatment
failure. However, this was not conrmed in sub-
sequent, larger series (Raimondi et al., 1996;
Moorman et al., 2003). Among the common struc-
tural abnormalities in high hyperdiploid ALL,
only i(17q) has been correlated with poor out-
come in some (Pui et al., 1988a; Raimondi et al.,
1996) but not all studies (Forestier et al., 2000b;
Moorman et al., 2003). Furthermore, there
are rare instances of high hyperdiploid cases har-
boring the ALL-specic rearrangements t(1;19)
(q23;p13), t(9;22)(q34;q11), or 11q23 transloca-
tions. In such cases, the prognostic impact of the
translocation is believed to override the benecial
effect of the high hyperdiploidy, and they are
hence usually not included in this karyotypic sub-
group (Forestier et al., 2000b; Moorman et al.,
2003).
GENETIC FEATURES
Obtaining Cytogenetic Data
As alluded to above, high hyperdiploid blast
cells are notoriously difcult to culture in vitro,
something that explains the fact that many cases
present as karyotypically normal or cytogenetic
failures (Harrison et al., 2005). Thus, to identify
all high hyperdiploid ALL alternative methods,
such as interphase FISH and DNA index analy-
ses, are mandatory (Look et al., 1982; Smets
et al., 1985; Berger et al., 1994; Martin et al.,
1996; Kasprzyk and Secker-Walker, 1997; Ritter-
bach et al., 1998; Nordgren et al., 2002; Pere z-
Vera et al., 2004; Nygaard et al., 2006). The dif-
culties in culturing also explain the lack of high
hyperdiploid cell lines; to the best of our knowl-
edge, there is only one established cell line
available (MHH-CALL-2) (Tomeczkowski et al.,
1995). Unfortunately, this precludes many in-
depth functional studies of high hyperdiploid
ALL.
Numerical Chromosome Aberrations
On the basis of conventional chromosome
banding analyses, it is quite clear that there is a
nonrandom pattern of chromosomal gains in high
hyperdiploid ALL, with additional copies of chro-
mosomes X, 4, 6, 10, 14, 17, 18, and 21 being
present in more than half of the cases (Fig. 4).
Chromosomes 8 and 5 are gained in 40% and
30%, respectively, whereas all other chromosomes
are supernumerary in only 1020%. As seen in
Figure 4, chromosome 21 is most frequently
gained; three or more copies are found in 90%
of cases. However, it should be emphasized that
even this high frequency is an underestimate:
FISH analyses reveal 21 in 100% of cases
(Moorman et al., 1996; Elghezal et al., 2001;
Paulsson et al., 2005). Hence, we would like to
suggest that gain of this chromosome is a sine
qua non for high hyperdiploid ALL.
By chromosome banding analysis, chromosome
21 is tetrasomic, sometimes even pentasomic, in
60% of cases (Fig. 4); using FISH this frequency
increases to 85% (Elghezal et al., 2001; Paulsson
et al., 2005). The remaining numerical changes
are usually trisomies, but tetrasomies do occur, in
particular involving chromosomes X, 14, and 18
(Heerema et al., 2007; Fig. 4). In contrast, monos-
omies are seldom, if ever, seen (Mitelman et al.,
2009).
The rare high hyperdiploid ALL originating
via a near-haploid clone (see below) harbor only
disomies and tetrasomies, with the latter most
often being tetrasomies X, 14, 18, and 21. They
can hence be distinguished cytogenetically quite
easily, even in the absence of the near-haploid
clone (Onodera et al., 1992a).
Structural Chromosome Aberrations
Approximately 50% of high hyperdiploid ALL
harbor cytogenetically identiable structural chro-
mosome aberrations in addition to the chromo-
somal gains (Groupe Francais de Cytoge ne tique
He matologique, 1993; Raimondi et al., 1996;
Forestier et al., 2000a; Moorman et al., 2003). In
addition, further structural changes are frequently
found when cases are analyzed with multicolor
FISH (Elghezal et al., 2001; Nordgren et al.,
2001; Paulsson et al., 2005).
Balanced chromosome aberrations
In the Mitelman Database of Chromosome
Aberrations in Cancer (Mitelman et al., 2009), 5%
of high hyperdiploid ALL carry balanced abnor-
malities, mainly translocations. In approximately
half of these, well-known ALL-associated tran-
slocations, most often t(1;19)(q23;p13) or t(9;22)
(q34;q11), are seen; such cases are associated
with the same chromosomal gains as high hyper-
diploid ALL in general, with the exception that
trisomy 2 is quite frequent in t(9;22)-positive
high hyperdiploid ALL (Mitelman et al., 2009).
It should be noted that none of the remaining
balanced rearrangements identied to date have
Figure 4. Chromosome gains in 414 high hyperdiploid B-lineage ALL (<18 years, modal chromosome
number 5167, not including incomplete karyotypes) reported in the literature (Mitelman et al., 2009).
Xf denotes gain of the X chromosome in females; Xm in males. Trisomy and Tetrasomy of Xm and
Y correspond to one and two extra copies of these chromosomes, respectively.
been recurrent, something that may argue against
the presence of a common fusion gene in this
cytogenetic subgroup.
Unbalanced chromosome aberrations
Most structural chromosome changes in high
hyperdiploid ALL are unbalanced, i.e., result in
gain or loss of genetic material. The most com-
mon are partial gains of 1q, deletions of 6q, and
isochromosomes of 7q and 17q (Pui et al., 1992;
Raimondi et al., 1996; Moorman et al., 2003).
Gain of 1q, via either duplications or unbal-
anced translocations, is found in 1015% of high
hyperdiploid cases (Groupe Francais de Cytoge -
ne tique He matologique, 1993; Raimondi et al.,
1996; Moorman et al., 2003). Recently, detailed
genetic and expression analyses revealed up-regu-
lation of ve genes (B4GALT3, DAP3, RGS16,
MEM183A, and UCK2) located in the minimally
duplicated 57 Mb segment at 1q2232.3 (Davids-
son et al., 2007), but it remains to be seen
whether this overexpression is pathogenetically
important.
Approximately 5% of high hyperdiploid ALL
harbor deletions involving the long arm of chro-
mosome 6 (Raimondi et al., 1996; Moorman
et al., 2003). Interestingly, Moorman et al. (2003)
noted that 6q deletions were usually independent
of 1q gains, which could suggest that these abnor-
malities represent alternative leukemogenic path-
ways. As of yet, no minimally deleted region on
6q has been identied in high hyperdiploid ALL
using G-banding or FISH. Furthermore, genome-
wide array-based analyses have not disclosed any
recurrent microdeletions on 6q (Paulsson et al.,
2006; Davidsson et al., 2007; Kuiper et al., 2007;
Mullighan et al., 2007; Strefford et al., 2007).
Thus, the biological impact of 6q deletions
remains unclear.
An i(7q) is present in 12% of high hyper-
diploid cases (Pui et al., 1992; Martineau et al.,
1996). Although usually denoted isochromosome,
FISH mapping has shown that it actually is an
isodicentric aberration with breakpoints in
7p11.2. No known gene is located in the break-
point region, indicating that i(7q) does not result
in a fusion gene and that the functional outcome
is the resulting loss of 7p and/or 7q duplication
(Schaad et al., 2006).
Between 2% and 5% of high hyperdiploid ALL
have been reported to harbor i(17q) (Martineau
et al., 1996; Raimondi et al., 1996; Moorman
et al., 2003). Since trisomy 17 is one of the char-
acteristic numerical anomalies in high hyperdi-
ploid cases (Fig. 4), it is noteworthy that 17 and
i(17q) seems to be mutually exclusive (Mitelman
et al., 2009). This may indicate that the pathoge-
netic consequence of trisomy 17 is gain of the
long arm.
Fusion Genes
As mentioned earlier, ALL-specic transloca-
tions resulting in fusion genes are occasionally
detected in high hyperdiploid cases. To date,
only four different chimeric genes, namely BCR/
ABL1 (Heerema et al., 2004), ETV6/RUNX1 (For-
estier et al., 2007), TCF3/HLF (Inukai et al.,
2007), and TCF3/PBX1 (Troussard et al., 1995),
have been identied in high hyperdiploid ALL.
It should be emphasized that cases with these
fusions are extremely rare, most likely comprising
less than 1% of the high hyperdiploid subgroup.
Interestingly, as regards TCF3/PBX1 several
investigators have noted that high hyperdiploid
ALL with t(1;19)(q23;p13) or der(19)t(1;19)
(q23;p13) rarely expresses this fusion transcript,
in contrast to the vast majority of t(1;19)-positive
non-high hyperdiploid ALL (Privitera et al.,
1992; Gaynon et al., 1997; Barber et al., 2007).
The reason for this remains unknown, but may
be due to different genomic breakpoints in the
TCF3 and PBX1 genes, as has been detected in a
few t(1;19)-positive ALL (Paulsson et al., 2007).
Alternatively, the 1q23 and 19p13 breakpoints
may involve other genes.
Thus, there is no known fusion gene speci-
cally associated with high hyperdiploid ALL to
date. Whether this reects evidence of absence
or absence of evidence is presently not clear.
The fact that there are no recurrent translocations
in high hyperdiploid ALL, with the exceptions
mentioned earlier, could suggest a true absence
of chimeric genes in this subgroup. Furthermore,
breakpoint mapping of inversions, insertions, and
translocationsbalanced as well as unbalanced
in high hyperdiploid cases reveals no pronounced
clustering of breaks, apart from the ones associ-
ated with t(1;19), t(9;22), and t(12;21) (Fig. 5).
However, the presence of fusion genes generated
through as yet unknown rearrangements in high
hyperdiploid cases cannot be excluded.
Microdeletions
With the advent of various array-based high-
resolution screening techniques, it has become
increasingly apparent that microdeletions are a
characteristic feature of ALL in general (Kuiper
et al., 2007; Mullighan et al., 2007; Paulsson
et al., 2008a). This also holds true for high hyper-
diploid cases, although the overall frequency of
such cryptic deletions seems to be lower than in
most other genetic ALL subgroups (Mullighan
et al., 2007). Using FISH or genome-wide arrays,
the loci thus far shown to be recurrent targets of
microdeletions in high hyperdiploid ALL are
located at 7p12.2 (IKZF1), 9p21.3 (CDKN2A),
9p13.2 (PAX5), 12p13.2 (ETV6), 13q14.2 (RB1),
and 19p13.3 (TCF3) (Mart nez-Ram rez et al.,
2001; Nordgren et al., 2002; Paulsson et al., 2006;
Figure 5. Breakpoint distribution of inversions, insertions, and
translocationsbalanced as well as unbalancedin 505 high hyperdi-
ploid B-lineage ALL (<18 years, modal chromosome number 5167)
reported in the literature (Mitelman et al., 2009). The breakpoint
clusters seen at 1q23, 9q34, 12p13, 19p13, 21q22, and 22q11 corre-
spond to the well-known ALL-associated translocations
t(1;19)(q23;p13), t(9;22)(q34;q11), and t(12;21)(p13;q22).
Barber et al., 2007; Davidsson et al., 2007; Mul-
lighan et al., 2007; Strefford et al., 2007; Sulong
et al., 2009).
The chromosomes with recurrent microdele-
tions, i.e., chromosomes 7, 9, 12, 13, and 19, are
rarely gained in high hyperdiploid ALL, making
the deletions easily identiable by single nucleo-
tide polymorphism (SNP) array analyses. In
contrast, a microdeletion in one of the three
homologues of a trisomic chromosome could
prove difcult to detect by this technique. Thus,
the frequency of microdeletions in high hyperdi-
ploid ALL may well be an underestimate
because of the multiple gains present in these
cases.
Gene Mutations
Mutations in the FLT3, KRAS, NRAS, and
PTPN11 genes have been shown to be relatively
frequent in high hyperdiploid ALL, with activat-
ing FLT3 mutations being found in 1025%,
KRAS/NRAS mutations in 1530%, and PTPN11
mutations in 1015% (Armstrong et al., 2004;
Taketani et al., 2004; Tartaglia et al., 2004; Wie-
mels et al., 2005; Stam et al., 2007; Paulsson
et al., 2008b). The mutations are usually mutually
exclusive, something that may be due to the fact
that all four genes are involved in the RTK-RAS
signaling pathway. Taken together, a substantial
proportionapproximately one thirdof high
hyperdiploid cases harbors a FLT3, KRAS, NRAS,
or PTPN11 mutation (Paulsson et al., 2008b).
Copy Neutral Loss of
Heterozygosity/Uniparental Isodisomy
The term UPID, originally coined in the eld
of constitutional genetics, denotes the presence
of two identicalmaternal or paternalhomolo-
gous chromosomes. Quite recently, this phenom-
enon has also been observed in neoplastic cells,
where it is detectable with SNP array analyses as
LOH without concurrent copy number changes
(Raghavan et al., 2005). These acquired aberra-
tions may either involve whole chromosomes
(wUPID) or parts of chromosomes (pUPID). In
acute myeloid leukemia (AML) and chronic mye-
loproliferative disorders, UPIDs have been shown
to lead to homozygosity for mutations in genes
such as CEBPA, FLT3, and JAK2 (Fitzgibbon
et al., 2005; Baxter et al., 2005). In ALL, a similar
mechanism renders CDKN2A deletions homozy-
gous in 9p (Mullighan et al., 2007; Kawamata
et al., 2008; Paulsson et al., 2008a).
Although there are a few examples of pUPIDs
in high hyperdiploid ALL, in particular for 9p
(Mullighan et al., 2007), they seem to be less
common in this subtype as compared with pediat-
ric ALL in general (Kawamata et al., 2008). The
reason for this is unknown. In contrast, there
appears to be an overrepresentation of wUPIDs
in high hyperdiploid cases (Kawamata et al.,
2008). As discussed below, this most likely
reects the underlying mechanism behind the
hyperdiploidy and may not be pathogenetically
important as such.
Epigenetic Changes
The eld of epigenetics in cancer, including
DNA methylation and histone modications, has
expanded dramatically in the past few years.
Although several groups have investigated hyper-
methylation of tumor suppressor genes in child-
hood ALL, only few have stratied data
according to genetic subtypes; no histone modi-
cation study has been published. Thus far, the
promoters of the following 19 genes have been
reported to be targeted by CpG methylation in
some high hyperdiploid ALL: APC, CADM1,
CD44, CDH13, CDKN1A, CDKN2B, CHFR,
DKK3, ESR1, FHIT, GATA5, MSH6, PAX6,
RARB, THBS1, TIMP3, TP73, WNT5A, and WT1
(Roman-Gomez et al., 2002, 2004, 2007; Zheng
et al., 2004; Paulsson et al., 2009). Of these,
CADM1, ESR1, FHIT, RARB, and WNT5A are
hypermethylated in more than 50% of cases.
Taken together, aberrant methylation of tumor
suppressor gene promoters seems to be a com-
mon phenomenon in high hyperdiploid ALL
(Paulsson et al., 2009).
Is High Hyperdiploid ALL Karyotypically
Stable or Not?
Chromosomal instability, detectable as cell-to-
cell variation in chromosomal content and the
presence of multiple subclones, is a characteristic
feature of many malignant disorders. On the basis
of chromosome banding analyses, subclones
usually differing from the stemline by one to
three additional chromosomes or structural rear-
rangementsare seen in 1520% of high hyper-
diploid ALL (Raimondi et al., 1996; Mitelman
et al., 2009), but since only one subclone is found
in most instances they probably reect clonal
evolution rather than karyotypic instability. In
contrast, there are some reports suggesting that
cell-to-cell variation, as detected with interphase
FISH analyses of the most common trisomies and
tetrasomies, is quite frequent (Betts et al., 2001;
Blandin et al., 2008). However, our own experi-
ence does not support this conclusion; only rarely
do we nd signicant differences in interphase
FISH signal patterns in high hyperdiploid ALL
(unpublished observation). Hence, further studies
are clearly needed to determine whether high
hyperdiploid ALL is karyotypically stable or not.
It should be noted that investigations of IGH@
rearrangements, performed as part of minimal re-
sidual disease analyses, quite often detect appa-
rent oligoclonality. However, in the vast majority
of cases such results can be explained by the fre-
quent occurrence of trisomy or tetrasomy 14,
leading to additional IGH@ alleles. Thus, mini-
mal residual disease analyses do generally not
provide any evidence for true oligoclonality in
high hyperdiploid ALL (Csinady et al., 2009).
PRENATAL ORIGIN
Almost half a century ago, MacMahon and
Levy (1964) reported that childhood leukemia
could have a prenatal origin, a proposition based
on twin studies showing that monozygous twins
are at substantial risk of concordance for this dis-
ease. Clarkson and Boyse (1971) developed this
idea further by suggesting that the high concord-
ance rate could represent only one occurrence of
leukemianot twowith the leukemic cells
circulating into the other twin through shared
placental vessels. This has since been clearly
demonstrated by the identication of identical
clonotypic breakpoints in concordant leukemias
characterized by various ALL-associated fusion
genes. In addition, chimeric genes have also been
detected in retrospective analyses of archived
neonatal blood spots from children who later
developed ALL. Thus, many pediatric ALL, or
rather preleukemic clones, arise in utero, with
additional postnatal events, most likely genetic
changes, being necessary for overt disease
(Greaves, 2005).
As regards high hyperdiploid ALL, the lack of
leukemia-specic fusion genes precludes similar
analyses of clone-specic breakpoints. However,
there is ample evidence for a prenatal origin of
also this genetic subgroup. First, Yagi et al.
(2000), Taub et al. (2002), Maia et al. (2004), and
Gruhn et al. (2008) demonstrated clonotypic
IGH@ rearrangements in Guthrie cards from
patients who later developed high hyperdiploid
ALL. Second, Panzer-Gru mayer et al. (2002), tak-
ing into account the fact that the IGH@ gene is
located on chromosome 14, showed that three
different IGH@ rearrangements and hence 14
were present already at the time of birth, strongly
suggesting that trisomy of at least this chromo-
some had taken place in utero. Third, Maia et al.
(2003) reported shared IGH@ rearrangements,
and similar chromosomal gains, in a pair of mono-
zygous twins with high hyperdiploid ALL.
Finally, Maia et al. (2004) supplied direct evi-
dence for the presence of trisomies in utero.
They investigated a child with high hyperdiploid
ALL who, by chance, happened to have had his
cord blood cells collected and frozen at birth,
and showed by interphase FISH analyses that
CD34CD19 cord blood cells harbored triso-
mies for chromosomes 15 and 17, as did the
blasts at diagnosis of ALL. Taken together, these
ndings show that hyperdiploidy is a prenatal
event in at least some cases of childhood ALL
and provide strong support for the possibility that
all such cases arise in utero.
CELL OF ORIGIN
Cancer stem cells, the existence of which was
suggested already in the early 1960s (Bruce and
Van Der Gaag, 1963), have received much atten-
tion during recent years, and it is now generally
accepted that hematologic malignancies are sus-
tained by leukemic stem cells capable of both
initiating and maintaining the disease. In leuke-
mias, the presence of different gene fusions, for
example ETV6/RUNX1, in well-dened cell popu-
lations has been used to identify the affected lin-
eages, hence providing circumstantial evidence
for candidate leukemia stem cells (Castor et al.,
2005).
Only few studies have focused on the cell of
origin in high hyperdiploid ALL. Larramendy
et al. (1995), using the morphology-antibody-
chromosomes technique and interphase FISH for
trisomic chromosomes, investigated ve high
hyperdiploid ALL and found that the gains were
restricted to cells expressing lymphoid markers in
four cases. In the remaining ALL, also glyco-
phorin A-positive (GPA) cells harbored the tris-
omy. Since these cells were morphologically
normal maturing erythroblasts, aberrant GPA
expression on lymphoblasts was considered
unlikely. They thus concluded that high
hyperdiploid ALL, at least in some instances,
may be a stem cell disease. Support for this con-
clusion was provided by Quijano et al. (1997),
who analyzed immunophenotypically character-
ized populations with interphase FISH for one or
two of the gained chromosomes and found that
CD34CD33CD38CD19 cells, i.e., the
primitive compartment that in normal bone mar-
row contains the stem cells, were trisomic in 25%
of the high hyperdiploid cases. However, Kaspr-
zyk et al. (1999), investigating B (CD19), T
(CD3), myeloid (CD13), and erythroid
(GPA) cells with interphase FISH, detected
trisomies only in the B cells, suggesting that high
hyperdiploidy arises in a lymphoid-committed
progenitor cell, although a pluripotent stem cell
origin with subsequent lineage restriction could
not be excluded. Although the latter possibility
still remains and further studies are denitely
needed, one should note that the high cure rate
of high hyperdiploid ALL with chemotherapy
alone would indicate that it does not originate in
a hematopoietic stem cell.
FORMATION
An important as well as intriguing question is
how the cell becomes high hyperdiploid. Theo-
retically, hyperdiploidy may arise through four
different mechanisms: (a) by initial near-haploidy
followed by doubling of the chromosomes, (b) by
tetraploidization with subsequent chromosome
losses, (c) by sequential gains of chromosomes in
consecutive cell divisions, or (d) by a simultane-
ous gain of chromosomes in a single abnormal mi-
tosis (Fig. 6) (Onodera et al. 1992b). Since we
cannot directly observe a high hyperdiploid ALL
in statu nascendi, evidence for and against the
above mechanisms is by necessity circumstantial;
investigations of allelic ratios of loci on tetrasomic
chromosomes and of wUPID frequencies may
provide valuable information (Fig. 6).
Near-Haploid Pathway
Near-haploidy (2529 chromosomes) is a rare
but recurrent cytogenetic feature of childhood B-
lineage ALL that is similar to high hyperdiploid
ALL in that a specic pattern of numerical
changes is seen, with most cases retaining diso-
mies for 21, X/Y, 14, and 18 (Harrison and
Johansson, 2009). However, in contrast to clas-
sic high hyperdiploid cases, near-haploid ALL is
associated with a dismal prognosis (Brodeur et al.,
1981; Gibbons et al., 1991; Harrison and Johans-
son, 2009).
Since the mid 1970s, it has been known that
near-haploid cases may harbor two clones: one
with a near-haploid chromosomal content and
one with a high hyperdiploid karyotype repre-
senting an exact duplicate of the stemline
(Kessous et al., 1975; Oshimura et al., 1977). Sub-
sequent investigations have shown that such
related clones are quite common in near-haploid
ALL; for example, Harrison et al. (2004) reported
a frequency of 65%. This has raised the possibil-
ity that some high hyperdiploid cases may origi-
nate as near-haploid, with subsequent duplication
of chromosomes and loss of the original stemline,
at least at the cytogenetic level (Brodeur et al.,
1981; Gibbons et al., 1991; Onodera et al., 1992a).
High hyperdiploid ALL arising via a near-hap-
loid state is cytogenetically distinct, being charac-
terized by the presence of only disomies and
tetrasomies; trisomies are rarely, if ever, seen
(Mitelman et al., 2009). Furthermore, such cases
have wUPIDs for all disomic chromosomes and
2:2 allelic ratios on all tetrasomic chromosomes
(Fig. 6A). Onodera et al. (1992a) showed that all
loci at disomic chromosomes displayed LOH, in-
dicative of wUPIDs, in a high hyperdiploid case;
a similar case has also been reported by us
(Paulsson et al., 2005). Furthermore, analysis of
the data set published by Mullighan et al. (2007),
including 39 high hyperdiploid ALL, reveals one
additional case. Also, FISH studies have revealed
near-haploid clones in interphase cells in some
high hyperdiploid cases (Ma et al., 1998; Stark
et al., 2001). Hence, it is clear that a proportion
of high hyperdiploid ALL originates through a
near-haploid pathway. However, it is equally
clear that most cases do not. As described in
detail below, the vast majority of high hyperdi-
ploid cases display retained heterozygosity of the
disomic chromosomes, in effect excluding a near-
haploid route. Furthermore, most gains in high
hyperdiploid ALL are trisomies (Fig. 4).
Finally, we would like to stress that the clinical
differences between near-haploid and high hyper-
diploid ALL makes it incumbent upon diagnostic
laboratories to identify the rare near-haploid cases
masquerading as high hyperdiploid ALL to
ensure correct risk stratication.
Tetraploid Pathway
A second possible mechanism leading to high
hyperdiploidy is initial tetraploidy with subsequent
Figure 6. Four possible mechanisms for the formation of high
hyperdiploidy. (A) Doubling of a near-haploid set of chromosomes,
resulting in whole chromosome uniparental isodisomies (wUPIDs) for
all disomies and 2:2 allelic ratios for all loci on tetrasomic chromo-
somes. (B) Initial tetraploidization with subsequent loss of chromo-
somes, resulting in wUPIDs for approximately one third of the
disomic chromosomes and 2:2 allelic ratios for all loci on tetrasomic
chromosomes. (C) Sequential gains of chromosomes in consecutive
cell divisions, resulting in no wUPIDs and 3:1 allelic ratios, corre-
sponding to triplication of one of the homologues and retention of
the other, for approximately two thirds of the tetrasomic chromo-
somes. (D) Simultaneous gain of chromosomes in a single abnormal
mitosis, resulting in no wUPIDs and 2:2 allelic ratios for all loci on
tetrasomic chromosomes. This gure was originally published in
Blood. Paulsson K, Panagopoulos I, Knuutila S, Jee KJ, Garwicz S,
Fioretos T, Mitelman F, Johansson B. Formation of trisomies and their
parental origin in hyperdiploid childhood acute lymphoblastic leukae-
mia. Blood. 2003;102:30103015, VC
the American Society of
Hematology.
loss of chromosomes. The allelic ratios of loci on
tetrasomic chromosomes will be 2:2 since both
homologues have been duplicated. Furthermore,
when four homologues are reduced to two, on av-
erage one third of the resulting disomies will be
wUPIDs in the absence of selective forces (Fig.
6B).
Virtually all reported allelic ratios of tetrasomic
chromosomes in high hyperdiploid cases have
been 2:2 (Onodera et al., 1992b; Paulsson et al.,
2003, 2005; Haas et al., 2004). Since this is
expected also in cases arising via near-haploidy
and by a simultaneous gain of chromosomes (Fig.
6), this nding cannot be used to identify cases
originating by the tetraploid pathway. Hence, the
pattern of wUPIDs is essential. A total of 52 high
hyperdiploid cases with SNP array or microsatel-
lite data on all disomies have been reported (Irv-
ing et al., 2005; Paulsson et al., 2005; Mullighan
et al., 2007). Of these, 30% displayed a pattern
of wUPIDs consistent with a tetraploid pathway,
but this does not by necessity reect the true fre-
quency of cases originating via tetraploidy. First,
a case arising through a different mechanism may
subsequently acquire wUPIDs, in particular if
they provide a selective advantage. However, the
reported wUPIDs have generally involved differ-
ent chromosomes, making selection for a specic
mutated gene or an imprinted region unlikely.
Second, in cases with high modal chromosome
numbers, lack of wUPIDs may simply reect the
fact that only few disomies are present, making it
impossible to exclude a tetraploid pathway.
Nevertheless, the observed frequency of 30% is
the best estimate of the occurrence of this
mechanism.
Sequential Gains
Another putative pathway to hyperdiploidy is
sequential gains of chromosomes in consecutive
cell divisions (Fig. 6C). This is an attractive pos-
sibility, because it ts well with the current para-
digmatic view of clonal evolution in malignant
disorders. However, it is not supported by nd-
ings at the cytogenetic level; as mentioned ear-
lier, most high hyperdiploid ALL do not display
subclones (Raimondi et al., 1996; Mitelman et al.,
2009). At the molecular level, high hyperdiploidy
formed via this pathway is expected to display
allelic ratios of 3:1corresponding to triplication
of one of the homologues and retention of the
otherfor approximately two thirds of the tetra-
somic chromosomes and no wUPIDs (Fig. 6C).
As regards the latter, 70% of high hyperdiploid
cases do not harbor any wUPIDs (Irving et al.,
2005; Paulsson et al., 2005; Mullighan et al.,
2007), something that would agree with sequen-
tial gains. However, we know of only two cases
where 3:1 allelic ratios for tetrasomies have been
observed (Onodera et al., 1992b; Paulsson et al.,
2005). Taken together, while there may be rare
cases arising through sequential gains in consecu-
tive cell divisions, this mechanism can be
excluded in the vast majority of cases.
Simultaneous Gain
Intuitively, the fourth and nal pathway
simultaneous gain of all extra chromosomes in a
single abnormal cell divisionmay seem quite
unlikely, not least considering the very charact-
eristic and nonrandom pattern of additional
chromosomes. However, available data actually
support this mechanism for the majority of high
hyperdiploid ALL: the expected pattern would
be a 2:2 allelic ratio of loci on tetrasomic chromo-
somes and no wUPIDs (Fig. 6D), and this is
what is found in most cases (Onodera et al.,
1992b; Paulsson et al., 2003, 2005; Haas et al.,
2004; Irving et al., 2005; Mullighan et al., 2007).
Thus, in all practice high hyperdiploidy arises
either via a tetraploid pathway (30% of cases)
or by a simultaneous gain (70% of cases).
PATHOGENETIC IMPACT OF
HIGH HYPERDIPLOIDY
As for trisomies and tetrasomies in hematologic
malignancies in general, next to nothing is known
about how high hyperdiploidy results in ALL. In
fact, there is evidence to suggest that it is not by
itself sufcient for leukemogenesis; additional
genetic alterations may be needed for overt dis-
ease. Indeed, it is not even known whether all
trisomies/tetrasomies are necessary; the variation
in chromosomal content may suggest that they
are not, as would the fact that sequential gains
are very rare (see above). Perhaps some of the
gains, in particular the less frequent ones, are epi-
phenomena in the sense of innocent bystanders
that are tolerated but do not provide a selective
edge. Even so, some of the extra chromosomes
are undoubtedly pathogenetically important, with
possible leukemogenic consequences including
mutated genes on the duplicated chromosomes,
gains of imprinted loci, and gene dosage effects.
High Hyperdiploidy is Not Sufcient to
Cause Leukemia
As discussed earlier, several lines of evidence
comprising clonotypic IGH@ rearrangements, con-
cordant high hyperdiploid ALL in twins, and the
presence of trisomic cells in cord bloodstrongly
suggest that high hyperdiploidy frequently, possi-
bly always, occurs in utero (Yagi et al., 2000; Pan-
zer-Gru mayer et al., 2002; Taub et al., 2002; Maia
et al., 2003, 2004; Gruhn et al., 2008). However,
among the 22 patients in whom a prenatal origin
has been demonstrated, the median age at ALL di-
agnosis has been 2 years and 10 months, with the
oldest being 14 years old. Although we cannot
exclude the possibility that the cells investigated
in the aforementioned studies had not yet acquired
high hyperdiploidyfor most of the cases only clo-
notypic IGH@ rearrangements were demon-
stratedthe rather long latency period
nevertheless indicates that high hyperdiploidy is
not sufcient to cause leukemia; additional genetic
aberrations are necessary for overt disease. These
may include structural chromosome aberrations,
microdeletions, gene mutations, and epigenetic
changes. However, the temporal order of the vari-
ous genetic hits in relation to the high hyperdi-
ploidy remains to be elucidated.
Pathogenetic ImpactDuplication of
Gene Mutations?
Some neoplasia-associated trisomies have been
shown to be associated with duplication of a
mutated gene residing on the gained chromo-
some, namely 4 and KIT in AML, 7 and Hras
in mouse skin squamous cell carcinomas, 7 and
MET in hereditary papillary renal carcinomas,
and 10 and RET in pheochromocytomas (Bian-
chi et al., 1990; Zhuang et al., 1998; Huang et al.,
2000; Beghini et al., 2004). However, we deem
this an unlikely pathogenetic basis for high
hyperdiploidy because it would imply that each
trisomic chromosome should harbor a mutated
gene. Furthermore, the fact that the vast majority
of tetrasomies in high hyperdiploid ALL display
a 2:2 allelic ratio, i.e., duplication of both parental
homologues (Onodera et al., 1992b; Paulsson
et al., 2003, 2005; Haas et al., 2004), strongly
argues against duplication of a specic mutation.
Pathogenetic ImpactGains of Imprinted Loci?
That imprinting effects may be of importance
in high hyperdiploid ALL was rst suggested by
Haas (1996), who hypothesized that gains of
maternally or paternally derived chromosomes
could result in deregulation of imprinted loci. If
correct, this would be detectable as a skewed
parental origin of the extra chromosomes (Haas
1996). We previously addressed this issue in a
series of high hyperdiploid ALL, including paren-
tal samples, and found no evidence for preferen-
tial duplication of maternal or paternal
chromosomes (Paulsson et al., 2003, 2005), a nd-
ing subsequently conrmed by Wilson and Mori-
son (2005). Thus, gains of imprinted loci can be
excluded as a pathogenetically important mecha-
nism in high hyperdiploid ALL.
Pathogenetic ImpactGene Dosage Effects?
A quite likely pathogenetic outcome of the
additional chromosomes in high hyperdiploid
ALL is gene deregulation, i.e., increased expres-
sion of genes located on the trisomic and tetraso-
mic chromosomes. In fact, most global gene
expression analyses have revealed a general up-
regulation of such genes in this cytogenetic sub-
group (Ross et al., 2003; Gruszka-Westwood
et al., 2004; Andersson et al., 2005). However, it
should be noted that not all genes behave in this
manner; some even display decreased expression
(Gruszka-Westwood et al., 2004; Andersson et al.,
2005). Furthermore, it remains unknown whether
the high transcription really translates into higher
protein levels. This notwithstanding, high hyper-
diploid ALL displays a specic gene expression
signature that allows a very high classication
accuracy (Yeoh et al., 2002; Qiu et al., 2003; Ross
et al., 2003; Andersson et al., 2005; van Delft
et al., 2005). Interestingly, a large proportion of
the class-dening genes is located on chromo-
somes 21 and X (Yeoh et al., 2002; Andersson
et al., 2005).
At present, next to nothing is known about
which pathways that are affected by the global
gene expression changes or their contribution to
the leukemogenesis of high hyperdiploid ALL.
However, considering the high frequency of
FLT3 mutations and the possible involvement of
folic acid metabolism in high hyperdiploid cases
(see above), it is noteworthy that FLT3 overex-
pression as well as a specic expression pattern of
genes involved in the folate pathway have been
reported in this genetic subgroup (Brown et al.,
2005; Kager et al., 2005). Thus, further studies
are denitely warranted. In addition, alternative
mechanisms for gene deregulation, such as global
epigenetic changes or aberrant microRNA expres-
sion proles, may also be important, but have not
been investigated in high hyperdiploid ALL to
date.
CONCLUSIONS AND FUTURE DIRECTIONS
Since the high hyperdiploid subgroup of child-
hood ALL was rst delineated in the early 1980s,
it has become clear that it comprises 2530% of
all pediatric B-lineage ALL; that it is associated
with a very favorable outcome; that the chromo-
some gains are nonrandom and most commonly
involve X, 4, 6, 10, 14, 17, 18, and 21; that addi-
tional genetic abnormalities are frequent, agree-
ing well with a multistep leukemogenic scenario;
that the preleukemic clone oftenperhaps
alwaysis present already at birth; that the high
hyperdiploid pattern may arise via different
mechanisms but most commonly through a single
abnormal cell division; and that deregulated
gene expression probably is pathogenetically
important.
However, many questions remain. Why does
high hyperdiploidy display such a strong correla-
tion with young age? What are the prenatal and
postnatal etiologic factors associated with high
hyperdiploidy and subsequent overt leukemia?
Why do 1520% of cases relapse? What is the
temporal order of the various cooperating
genetic eventstrisomies, structural chromosome
changes, microdeletions, mutations et cetera? Are
there other, as yet unidentied, genetic or epige-
netic changes, such as cryptic fusion genes or
methylation hotspots, promoting leukemogenesis?
At which stage of the hematopoietic hierarchy
does high hyperdiploidy arise? What are the exact
mechanisms underlying the formation of the high
hyperdiploid pattern? Are there biological or clin-
ical differences between cases originating via a
tetraploid pathway and by a simultaneous gain of
chromosomes? To answer all these questions is
truly a Herculean task, and this great challenge
will undoubtedly occupy scientists from different
elds of study for many years to come.
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GENES, CHROMOSOMES & CANCER 48:637660 (2009)

High Hyperdiploid Childhood Acute

strand-Grundstro m I, Buitenhuis M, Ram-

, Heldrup J, Behrendtz M, Panagopoulos I, Fioretos

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