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1426 R.B. Richardson / Leukemia Research 35 (2011) 1425–1431
Fig. 1. Schematic diagram of major activation (continuous lines) and suppression (dotted lines) regulatory pathways of a child’s defensive response to microbial infections.
Response timesto infectionare rapid(minutesto 4 h), intermediate (around 2 d),or slow (3 d or more). The bottom bar indicates potential effects on pre-leukemia cells. HPA:
hypothalamic-pituitary-adrenal; NK: natural killer;and see main text for other abbreviations.
by infectious diseases [10], as occurs in Burkitt lymphoma, the
premise of this paper is that the promotion of PBC-ALL is an aber-
rant immunological response to pre-natal infections, andespecially
post-natal infections that have a peak occurrence at 10 months old
in an affluent country such as the U.K. [11]. Intracellular pathogens
such as viruses, which invoke a particularly rapid innate immune
response, are the cause of approximately 90% of acute febrile ill-nesses in infants and young children [12]. There is a risk—especially
in neonates—that serious infections (including common extracel-
lular bacteria e.g., S. pneumoniae and H. influenzae) may put the
adaptive immune system and B-cells under proliferative stress
(Fig. 1).
The infective heat shock and lymphoid tissue recovery hypoth-
esis (herein called the ‘infective lymphoid recovery hypothesis’)
presented here proposes that pre-leukemic cells may be promoted
to overt PBC-ALL by common infections, primarily in young chil-
dren, according to the following etiologic process:
(a) hygienic conditions in infancy inhibit early immune priming,
thus reducing the efficacy of the secondary immune response
to later infections [13,14],(b) infectiousfevers induce expressionof heat shock proteins (HSP)
and pro-inflammatory T helper 1 (Th1) cell cytokines, both of
which are conducive to cell survival and a hypermutatable state
[15],
(c) cytokine activation of the hypothalamic–pituitary–adrenal
axis, resulting in infection-related glucocorticoid release and
transient involution of the thymus and other lymphoid organs,
causesa decline in antitumorimmunosurveillance and the mat-
uration arrest of B-cells,
(d) recurrent infections lead to cumulatively degraded stress
responses and higher homeostatic cytokine levels as the
body tries to reconstitute the atrophied/maturation-stalled
lymphoid tissue, thereby stimulating the proliferation of pre-
malignant precursor B-cells, and
(e) later release of Th2 cytokines augments a secondary and adap-
tive immune response,puttingadditionalproliferative stress on
bone marrow hematogones (benign B-lymphocyte precursors)
and pre-leukemic cells, thereby advancing overt leukemia.
The infective lymphoid recovery hypothesis is based on a three-
part methodology(Fig.2), andan extensive review of the associatedliterature, that in: Section 1 reconciles seemingly contradictory
protective and promoting evidence concerning infectious expo-
sure, hereafter called the ‘infection paradox’; Section 2 ascertains
the etiologic factors associated with individuals with congenital
syndromes who are susceptible to developing childhood leukemia,
especially PBC-ALL; and Section 3 f urther explores the evidence
for an infectious heat shock response and other factors identi-
fied that promote pre-leukemic cells to overt PBC-ALL. Lastly, the
infective lymphoid recovery hypothesis is compared with other
published hypotheses, demonstrating the ability of the infective
Fig. 2. The three major elements of the infective lymphoid recovery hypothesis.
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R.B. Richardson / Leukemia Research 35 (2011) 1425–1431 1427
lymphoid recovery hypothesis to explain certain PBC-ALL charac-
teristics, such as peak incidence at 2–5 years of age.
1. Infection paradox
This section provides an explanation for the often contrary sci-
entific evidence on the involvement and timing of infections in
PBC-ALL etiology. Epidemiological studies and hypotheses identify
a significant but low risk of childhood leukemia from in utero infec-tious exposure during pregnancy [7,16]. McKinney et al. [17] f ound
that, in British children, ALLwas stronglyassociatedwith post-natal
viral diseases (e.g., chicken pox, rubella, measles and influenza)
occurring within 6 months of birth, withthe latent period to malig-
nancy ranging from 2.5 years to 5.5 years. Children over the age of 9
diagnosed with lymphoid cancers were associated with 4 or more
episodes of illness (e.g., influenza). A later U.K. case control study
[18] f ound that children aged 2–5 years diagnosed with ALL had an
excess of clinically diagnosed (e.g., presence of fever) viral andbac-
terial infections in infancy, especially during the neonatal period
(less than 1 month old). Two or more infections caused ALL to be
diagnosed earlier than for a single episode.
The apparent importance of infective mechanisms in the pro-
motion of childhood ALL led Kinlen [19], Greaves [14], and
Schmiegelow et al. [20] to postulate the ‘population-mixing the-
ory’, the ‘delayed first exposure hypothesis’, and the ‘adrenal
hypothesis’, respectively; the latter is examined in the Discus-
sion. Kinlen’s population-mixing theory proposed that workers
moving to isolated communities expose immunologically naïve
infants to specific infections and a higher risk of ALL [19]. Greaves’
delayed first exposure (or ‘delayed infection’) hypothesis is based
on the necessity of an infectious challenge for the newborn’s
naïve immune system to mature and counter childhood ALL [14].
Accordingly, infants who experience a delayed exposure to infec-
tious agents are at greater risk of an abnormal lymphoproliferative
response. Support for Greaves’ hypothesis comes from studies
asserting that formal daycare (as compared to home care) and
increasing birth order provide infants with a significant protec-
tive effect against ALL due to an early, elevated infectious exposure[7,21,22]. Yet, as discussed above, there is also seemingly contrary
evidencethat multipleor prolonged episodes of common infections
in infancy promote the transition to overt ALL later in childhood
[17,18]. The infective lymphoid recovery hypothesis addresses this
infection paradox by presuming that mild infections early in life
prime the immune adaptive response, whereas later recurrent
infections in childhood provide the conditions conducive for the
accumulation of cooperating oncogenic mutations necessary for
the promotion of PBC-ALL [5].
2. Etiologic factors identified fromcongenital syndromes
andother conditions
Congenital syndromes and other conditions (e.g., irradiation)
that are associated with an excess risk of childhood leukemia
were examined in order to identify the etiologic factors that
increase vulnerabilityto acute myeloid leukemia (AML), andpartic-
ularly to PBC-ALL. Table 1 lists the relationship between childhood
leukemia and the following conditions: Down Syndrome (DS);
primary immunodeficiency disorders (i.e., ataxia–telangiectasia
and DiGeorge syndrome); chromosome fragility disorders (i.e.,
Bloom syndrome and Fanconi anemia); and Shwachman–Diamond
syndrome and neurofibromatosis (the latter arising from a tumor-
suppressor gene mutation) [23]. The association of childhood ALL
with lymphoid organ changes was reviewed to determine if a pos-
itive association was linked to a congenital (primary) feature or to
atrophy acquired due to (secondary) infection. Breastfeeding was
also considered because of its role in partially negating the risk of
childhood leukemia.
Ionizing radiation is the best-documented environmental risk
factor that is significantly linked to childhood leukemia. Even so,
past risk assessments of leukemia and bone cancer induced by
radionuclide intakes have been hampered by assuming the dose
and risk to quiescent and active (hematopoietic and mesenchymal)stem cells is the same [24]. The epidemiological evidence is gen-
erally positive for both in utero and post-natal exposure causing
excessive instances of ALL and AML, with a weaker association as
age increases [6,25,26]. In addition, high-dose treatments admin-
istered before 1950 to reduce purportedly enlarged thymuses in
infants led to an elevated incidence of thyroid cancer and leukemia
[27]. Even for low radiation doses of the whole body, there is the
potential for ALL to be initiated by DNA double strand breaks in
utero and promoted post-natally, perhaps by a heat shock response
that furthers inflammation and inhibits apoptosis [28].
Infections can be a concern in the chromosome fragility dis-
orders Bloom syndrome and Fanconi anemia, although thymus
abnormalities for either disorder are not prominent in the litera-
ture. Leukemia develops in about 10–15% of both Bloom syndromeand Fanconianemia patients.German[29] reports a similar number
of acute lymphocytic and myelogenous leukemia cases for Bloom
syndrome. There is little evidence of an ALL incidence peak at 2–5
years for either disorder. In Fanconi anemia patients, AML is the
dominant form of leukemia (>90% of cases) and is related to the
premature senescence of hematopoietic stem cells and the occur-
rence of myelodysplastic syndrome (MDS) [30,31]. This suggests
that senescence of the hematopoietic stem cell pool may promote
AML, yet inhibit the promotion of ALL.
Table1
Characteristics relevant to childhood leukemia are compared for various conditions and assessed as observed (√
) or not observed (no symbol) as a prominent feature in the
literature.
Conditions Prone to
infections
Abnormal (or absent)
thymus
Abnormal non-thymic
lymphoid tissue
Excessive ratesof ALL
with peak 2–5 y
Excessive rates of
‘non-PBC ALL’
leukemia
Ataxia–telangiectasia [33,34]√ √
(Mostly absent)√
S, L√
T-ALL
Breastfeeding (absence of) [36–38]√ √
Smaller√ √
AML
Bloom syndrome [29]√ √
AML
Congenital heart defects [32]√ √
(Absent)
DiGeorge syndrome [35]√
Down syndrome [39–42,48]√ √ √
BM, S , L√ √
AML
Fanconi anemia [30]√ √
BM√
AML
Infections (in utero and in infancy)
[16–18,59,61]
√ √ BM, S , L
√ √ AML
Ionizing radiation [6,25,27]√
High dose only√
BM, S, high doseonly√ √
AML
Neurofibromatosis [23]√ √
AML, JMML, T-ALL
Shwachman–Diamond syndrome [49]√
BM√
AML
ALL: acute lymphoblastic leukemia, AML: acute myeloid leukemia, BM:bone marrow, JMML: juvenile myelomonocytic leukemia, L: lymph,S: spleen, and T-ALL: T-cell ALL.
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1428 R.B. Richardson / Leukemia Research 35 (2011) 1425–1431
There are several athymic medical conditions, including con-
genital heart defects, which are present in about 1% of babies at
birth. Within weeks the thymus is generally removed surgically to
repair the heart. Young adults with congenital heart defects have
a T-cell profile similar to elderly non-affected adults 50 years their
senior [32]. The majority (80%) of ataxia-telangiectasia individuals
also have no thymus; for the 20% with the organ, it resembles that
of a fetus [33]. Hypoplasia of lymphoid tissue and infections are
common in ataxia–telangiectasia patients, who are also prone to
developing non-hematologic and hematologic neoplasms, includ-
ing T-cell ALL and AML [34]. The immunological abnormalities of
DiGeorge syndrome individuals and their susceptibility to recur-
rent infections may be attributed to congenital underdevelopment
of the thymus or, rarely, to its complete absence. B-cell matura-
tionandthe adult-like production of immunologlobulin-containing
cells does not normally take place in neonates without DiGeorge
syndrome, but surprisingly does take place in neonates with the
syndromewho lackT-suppressor activity[35]. ChildhoodALL is not
prominent in these conditions, and therefore it appears that infec-
tions in children who lack a functional thymus are not conducive
to the development of ALL.
Breastfeeding (as compared to formula feeding) can double
thymic size by 4 months of age, improve CD4+ and CD8+ T-
lymphocyte concentrations, and reduce the risk of respiratory tractinfections in infants by up to two-thirds [36,37]. A meta-analysis
of 14 case-control studies revealed that long-term breastfeeding
reduces the risk of childhood leukemia, particularly ALL; although
the results of individual studies are ambiguous probably due to
their small size [38]. These breastfeeding studies highlight the
importance of even modest changes in thymic size upon the post-
natal development of immunocompetence and ALL.
For most congenital syndromes susceptible to leukemia, there
is limited data on ALL subtypes and their relative risk; of these con-
ditions, DS children are the best studied. DS children are highly
vulnerable to respiratory tract infections and an increased occur-
rence of thymic aberrations [39]. Marked (T- and B-) lymphocyte
depletionhas also been observed in the spleenand lymph glandsof
DS infants perhaps due to congenital factors [40]. It is well knownthat individuals with DS have a greatly elevated risk of childhood
leukemia: the relative risks are about 10–30 times higher than
controls [39,41,42]. Neonates with DS exhibit a range of hemato-
logic abnormalities, including transient leukemia and MDS, both
of which can precede AML. For DS children, the frequency of ALL
is about one and a half times that of AML, as compared to 4:1 for
non-DS children [42].
The vulnerability of DS children to immunological defects and
PBC-ALL may be affected by additional copies of genes on chro-
mosome 21, such as the oncogene AML1, and genes of the HSP70
family and interferon (IFN) receptors [43]. Regarding the latter, DS
individuals exhibit increased levels of the Th1 pro-inflammatory
cytokine IFN- associated with stimulating the formation of com-
mon lymphoid progenitors [44,45]. IFN-inducible genes indicativeof a viral infection are highly expressed in the hyperdiploid PBC-
ALL variant that constitutes a large part of the incidence peak [46].
Trisomy 21 is present in the bone marrow of all DS individuals, and
it may not be a coincidence that it is also present in half of non-DS
childhood ALL cases [47]. Therefore, trisomy 21 could be involved
in promoting ALL in DS and non-DS children, as both groups have
a similar trend in ALL age-specific incidence rates [48]. A differ-
ence is that the DS peak incidence is more pronounced and the
promotion/latent period possibly shorter than for non-DS.
In summary, a high risk of bone marrow dysfunction is present
in children with chromosome breakage syndromes (i.e. ataxia
-telangiectasia, Bloom syndrome and Fanconi anemia), DS and
Shwachman-Diamondsyndrome [49]. These congenital syndromes
display segmental symptoms of accelerated ageing, as does MDS,
a disease that can advance to AML, but not ALL. Similarly, thymec-
tomy in congenital heart defect patients and the impaired thymic
processes in ataxia–telangiectasia, DiGeorge syndrome and DS,
prematurely age the immune system and downgrade the abil-
ity to countermand infections and tumors [32]. Nevertheless,
the apparent lack of excessive rates of ALL in children with
ataxia–telangiectasia, congenital heart defects, and DiGeorge syn-
drome implies that the absence or removal of an infant’s thymus
is not enough in itself to induce PBC-ALL (Table 1). DS studies
indicate an abnormal infective Th1 signaling response to an IFN--dependentimmunosurveillance mechanism.Therefore, etiologic
factors conducive to the promotion of childhood ALL appear to be
recurrent infections, followed by thymic atrophy, lymphoid tissue
abnormalities, sustained proliferative signaling and reconstitution
of lymphoid tissue.
3. Infective heat shock response and lymphoid tissue
recovery
Natural stressors,such as heat stress, malnutritionand infection,
can invoke a heat shock response. Evidence is presented below to
demonstrate that recurrent infective and heat shock responses in
the fetus or infant are linked to defective differentiation of bloodcells, overproduction of immature B-lymphocytes, and inhibition
of B-cell death—genetic hallmarks of PBC-ALL [5]. HSPs generated
by the host upon invasion by viruses and bacteria (or the bacteria’s
own HSPs) rapidly activate the innate immune system. This is fol-
lowed by a hypothalamic–pituitary–adrenal response [50], as well
as acute involution of the thymus (alternatively called ‘transient
involution’) and of other lymphoid organs and tissues.
A mutation in the gatekeeper p53 gene—the most common
mechanism by which a neoplasm escapes apoptosis—is weakly
associatedwith leukemia.Only 5% of childhoodALL cases at diagno-
sis exhibit p53 mutations, which is among the lowest p53 mutation
incidence of all cancers [51]. HSPs may be a more prevalent means
of avoiding cell death in leukemia. An elevated expression of HSPs
has been detected in various forms of leukemia (e.g., high constitu-tiveexpressionof HSP90 is associated withthe proliferationof ALL
cells) [52]. Small heat shock protein HSP27 isoforms are associated
with common ALL in a uniquely characteristic manner, as HSP27
is synthesized during both normal and abnormal development of
immature lymphoid cells at the pre-B-cell stage of differentia-
tion [53]. There is a greater frequency of human leukocyte antigen
(HLA) haplotypes and HLA-complex-linked HSP70 genes in boys
as compared to girls [54]. This, and males’ greater susceptibility
to infections and stress, may possibly influence the incidence of
childhood ALL being slightly higher in boys than in girls [55].
HSP60, HSP70, and HSP90 induce macrophages and other cells
to release Th1pro-inflammatory cytokines, including tumor necro-
sis factor- (TNF-), interleukin-2 (IL-2) and IL-12 [56]. About
two days after a heat shock response, Th1 cytokines stimulateincreased glucocorticoid secretion during the post-stress recov-
ery period, thereby causing transient involution of the thymus
and limiting over-activity by the immune and inflammatory path-
ways. Chronic (particularly bacterial) infections and heat shock
result in cumulative stress-induced weakening of the glucocorti-
coid receptor-mediated recovery response [57]. Thymic involution
and thymic lymphocyte depletion measured in fetuses and young
children have been shown to be related to the duration of pre-natal
and post-natal acute infections, respectively [58,59]. In addition,
limited atrophy in the spleen and lymph nodes was observed
in those who died after a period of acute illness [58,60]. These
anatomical findings show that after sustained pre- or post-natal
infections, there is cumulative degradation of lymphoid tissue
requiring reconstitution.
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R.B. Richardson / Leukemia Research 35 (2011) 1425–1431 1429
Infants experiencing infections exhibit thymic involution and
can be expected to have lesser immunosurveillance by CD4+ and
CD8+ cells, similar to formula-fed infants [36]. In addition, the
lower thymic function affects the ability to complete the B-cell
maturation process and to generate high-affinity memory cells
and antibody formation [61]. Hematogones make up on average
one-third of the bone marrow cells of living pre-term neonates
[62]. Normally, marrow lymphocyte maturation is probably trig-
gered by birth, with ten times fewer hematogones at 2–5 years
old. Hematogones are especially prominent in children exhibiting
a serious complication(e.g.,acute thrombocytopenicpurpura)after
viral infections such as measles and chicken pox [63]. Congenital
cytomegalovirus (CMV) infections are associated with post-natal,
excessive hematogones of immature benign cell types similar to
those characteristic of infant ALL (a distinct PBC-ALL group, most
with MLL gene rearrangements) that usually occurs in infants, 0–1
year old [64]. Further evidence of arrested bone marrow matu-
ration is provided by post-uterine CMV infections preceding the
observation of hematogones of PBC-ALL-like cell types [65]. There-
fore, perinatal infections seem to be an opportunistic mechanism
for bone marrow to undergo maturation arrest and acquire the
immunophenotypic aberrancies characteristic of PBC-ALL.
Key components of any PBC-ALL etiological hypothesis are the
biological mechanisms that can stimulate excessive B-cell prolif-eration. A B-cell response is not limited to bacterial infections; for
instance, the influenza virus induces IFN-mediated B-cell activa-
tion and the production of antiviral antibodies [66]. In addition,
respiratory syncytial virus—the principal etiologic agent of res-
piratory infections in infants and young children—provokes both
a heat shock and Th2 response [67]. There is also evidence that
dysregulation of the transforming growth factor- (TGF-) path-
way, a Th2 cytokine produced in response to infection and that
accelerates thymic involution, is involved in the promotion of TEL-
AML1-positive ALL [68].
Lastly, there is evidence of B-cell proliferative signaling by the
homeostatic agent IL-7, which is associated with infections and
reconstitutions of maturation-stalled or atrophied lymphoid tis-
sues. IL-7 serum levels are elevated after infections in general, andaugment reconstitution of the thymus and spleen [69,70]. Perhaps
related to DS’s congenital vulnerabilityto childhood ALL,IL-7 levels
aresimilarly raised in DS individuals aged 4–25years oldwho have
no acquired diseases [71]. IL-7 not only stimulates the proliferation
of normal B- and T-cell precursors and T-lymphocytes, but it also
acts as a growth factor for PBC-ALL and T-cell ALL [72].
In summary, the seemingly contradictory aspects of infection
and PBC-ALL risk have been explained; the etiological factors,
derived from conditions with varying susceptibility to childhood
leukemia, have been identified; and further evidence that supports
the infective lymphoid recovery hypothesis has been presented.
The hypothesis asserts that recurrent infection-driven heat shock
and lymphoid involution is followed by an IL-7-mediated immune
recovery that places increased proliferative pressure on immatureB-cells, which in turnpromotesthe transformationof pre-leukemic
cells into overt PBC-ALL.
4. Comparison of PBC-ALL etiological hypotheses
The adrenal hypothesis, as recently proposed by Schmiegelow
et al. [20], explains the lower risk of common ALL experienced
by children exposed to early infections by citing changes in the
hypothalamic–pituitary–adrenal axis. This theory maintains that
infections raise glucocorticoid (e.g., cortisol) levels, which effec-
tively induce apoptosis of thymocytes, reduce proliferative stress,
and lead to the apoptosis of pre-existing leukemic cells. Strong
evidence is given in support of the adrenal hypothesis—namely,
that the administration of glucocorticoid (either on its own or as
part of an anti-inflammatory, immunosuppressive and chemother-
apeutic ALL agent) can produce a four-log reduction of malignant
lymphoblasts in children [73]. However, the adrenal hypothesis
does not address the fact that after infection-mediated atrophy
of lymphoid tissue, there is reconstitution that puts proliferative
stress on apoptotic-resistant, pre-leukemic cells. Also, the adrenal
hypothesis only accounts for the first of two seemingly contra-
dictory mechanisms of the infection paradox—that infections can
provide both a protective and promotional mechanism in PBC-ALL
etiology [14,17–19].
The infective lymphoid recovery hypothesis, however, is able
to reconcile both components of the infection paradox. It asserts
that protection from PBC-ALL is afforded by early, mild infections
that prime an adaptive immune response. Any delay in this prim-
ing (more likely to occur in hygienic, socially isolated, and affluent
societies) places greater reliance, when defending against infec-
tious pathogens, on heat shock activation of the innate immune
responseandon a pro-inflammatory state. However,laterrecurrent
exposure to infections—especially in infancy—has an accumula-
tiveeffect on activationof the hypothalamic–pituitary–adrenal axis
and transient involution of lymphoid tissues, which may enhance
the selection of a resistant, pre-leukemic strain. The subsequent
reconstitution of lymphoid tissues places proliferating stress onhematogones and pre-leukemic cells.
Greaves [8] rightly states that any credible hypothesis on the
etiology of childhood ALL needs to explain why ALL incidence rates
in children increase by ∼1% per annum, and why the incidence
peak at 2–5 years is more prominent in affluent societies as com-
paredto populations withpoor socio-economic conditionsand high
child mortality rates [7,10,20,74]. One factor that should be con-
sidered is that in less-affluent or developing countries, families are
generally larger and live in closer quarters; this provides a par-
allel environment to the daycare centers in the developed world
that immunologically prime young children and protect against
childhood ALL [21,22]. Another factor likely influencing the low
ALL incidence rates in children of developing countries is their
high rate of breastfeeding [75], which furthers thymic enlarge-ment that improves the immunosurveillance of pre-leukemic cells
and lessens the need for lymphoid tissue reconstitution. On the
other hand, affluence and improvedhealthcare lead to moreinfants
surviving recurrent infectious episodes (especially important to
the more vulnerable, such as those with DS) [25] and living to
experience accumulated lymphoid tissue atrophy and recovery,
thereby putting greater proliferative stress on hematogones and
pre-leukemic cells. The infective lymphoid recovery hypothesis
predicts that this intense transformative pressure shortens the
promotion/latent period, concatenating the PBC-ALL diagnoses
towards late infancy (the period of maximum infection rates) [11]
and resulting in a steeper and more pronounced peak incidence.
The widely accepted hygiene hypothesis explains the elevated
incidence of allergies in developed countries based on lesser expo-sure to infections during early childhood [13]. It is compatible
with Greaves’ [14] hypothesis (as well as the infective lymphoid
recovery hypothesis), which contends that the risk of childhood
ALL is reduced by exposure to priming infections in early life.
Notwithstanding, Schmiegelow and colleagues [76] conducted a
meta-analysis of 11 case–control studies and found an inverseasso-
ciation between ALL and atopic allergies in children (e.g., asthma,
eczema, and hay fever). Similarly, DS cases susceptible to ALL are
associated with a significant deficit of asthma [41]. Allergies involve
an excessive Th2 anti-inflammatory response and class-switching
to enhance the production of IgE antibodies. A possible expla-
nation for the inverse relationship is that PBC-ALL is associated
more strongly with a heat shock mediated Th1 response and lym-
phoid tissue reconstitution, as compared to aTh2 response. Further
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1430 R.B. Richardson / Leukemia Research 35 (2011) 1425–1431
support for a Th1 response being linked to PBC-ALL is provided by
observations of malnourished children without infections from a
developing country, which generally have low incidences of ALL
[50]. Although starvation is associated with a heat shock response
these childrendo not haveelevatedlevels of serumcortisolandTh1
pro-inflammatory cytokines.
5. Predictions and conclusion
The infective lymphoid recovery hypothesis generates testable
predictions. One is that the risk of PBC-ALL will be generally
enhanced in those young children who experience recurrent infec-
tions and elevated levels of IL-7 indicating a lymphoid recovery.
Another prediction is that neonates and infants, compared to older
children, will exhibit a greater gain in the frequency of oncogenic
mutations due to infections [15]. Issues warranting further study
include determining if the protective and promotional facets of
the infection paradox apply differently to PBC-ALL immunologi-
cal (e.g., pro-B, pre-B) or cytogenetic variants, as suggested by high
virus-mediated INF- levels associated with the hyperdiploid sub-
type [46]. A better understanding of PBC-ALL etiology would be
gained from collecting further statistical data on ALL subtypes for
congenital syndromes and other vulnerable conditions.In conclusion, a significant aspect of the infective lymphoid
recovery hypothesis is that it appears to explain the infection para-
dox and the prominence of the ALL peak incidence as being due to
the shortening of the promotion/latent period by surviving multi-
ple infections andan over-expressive lymphoid-recovery response.
It is hoped thatthis hypothesis will encourage further research and
testing of the etiological process proposed, thereby leading to a
better understanding and treatment of common childhood ALL.
Acknowledgements
The author thanks Mel Greaves of The Institute of Cancer
Research, London, U.K.; Johann Hitzler of The Hospital for Sick Chil-
dren Research Institute, University of Toronto, Canada; and PatriciaMcKinneyof Universityof Leeds,U.K.for their review of earlydrafts.
The author also thanks Elizabeth Bond for careful proofreading of
this manuscript.
Funding source: None.
Contributions: Richard B. Richardson is the sole author and con-
tributor.
Conflict of interest : Richard B. Richardson has no conflict to
declare.
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