Leukemia Research 35 (2011) 14251431

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Leukemia Research
journal homepage: www.elsevier.com/locate/leukres

Invited review

Promotional etiology for common childhood acute lymphoblastic leukemia: The infective lymphoid recovery hypothesis
Richard B. Richardson
Radiological Protection Research and Instrumentation Branch, Atomic Energy of Canada Limited (AECL), Chalk River Laboratories, Chalk River, ON K0J 1J0, Canada

a r t i c l e

i n f o

a b s t r a c t
This paper speculates on the role of infection in modifying a young childs risk of promoting precursor B-cell acute lymphoblastic leukemia (ALL). It is suggested that the heat shock instigated by infections, particularly in infancy, stimulates Th1 pro-inammatory cytokines and an apoptosis-inhibitory environment. This infective stress also increases the number of cooperating oncogenic mutations in pre-leukemic cells, especially if the primary adaptive immune response is delayed. The glucocorticoid release that follows leads to acute thymic involution, a decline in antitumor immunity, and maturation arrest of Blymphocytes. The infective lymphoid recovery hypothesis addresses an apparent contradictionthat a non-hygienic environment primes the adaptive immune response and is protective against childhood ALL, while multiple infections occurring later increase the risk of childhood ALL. In afuent (compared to less-afuent) societies, the characteristic ALL incidence peak in early childhood, and the shortened time to diagnosis, arise from surviving recurrent infections and the accumulated loss and recovery of lymphoid tissue. Evidence supporting the hypothesis, such as the role of lymphoid tissue reconstitution cytokines that stimulate proliferation stress on B-cell progenitors, comes from the study of children with congenital syndromes that are susceptible to leukemia. Crown Copyright 2011 Published by Elsevier Ltd. All rights reserved.

Article history: Received 16 April 2011 Received in revised form 12 July 2011 Accepted 18 July 2011 Available online 7 September 2011 Keywords: Acute lymphoblastic leukemia Child Etiology Heat shock Immune reconstitution Infections

Contents 1. 2. 3. 4. 5. Infection paradox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1427 Etiologic factors identied from congenital syndromes and other conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1427 Infective heat shock response and lymphoid tissue recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428 Comparison of PBC-ALL etiological hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429 Predictions and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430

Precursor B-cell acute lymphoblastic leukemia (PBC-ALL), also known as common ALL, is the most prevalent form of ALL in children (115 years), with an incidence that characteristically peaks between 2 years and 5 years of age [1]. Another ALL subset, T-cell ALL, is diagnosed uniformly throughout childhood. Although cancer is generally a multistage process, there is merit in explaining ALL in terms of a two-stage initiation-promotion model, with initiation mutations mainly taking place in utero [2,3]. Childhood PBC-ALL is most commonly associated with high-hyperdiploid leukemic

Corresponding author. Tel.: +1 613 584 3311x44755. E-mail address: Richard.Richardson@mcgill.ca

clones (30%), as well as the fusion genes t(12;21) [TEL-AML1] and t(1;19) [E2A-PBX1], among other genetic aberrations. Covert leukemic clones initiated pre-natally from primitive hematopoietic cells are present both in those who do, and those in the majority who do not, develop the disease [4]. These pre-leukemic cells require additional cooperating oncogenic lesions to be promoted to an overt and full leukemic phenotype [5]. The range of epidemiological factors that are associated with ALL suggests a multifactorial promotional etiology with a potential genetic component. Risk factors associated with childhood ALL include ionizing radiation, certain chemotherapy agents, pesticides, and low birth order (e.g., being a rst-born) among others [68]. Nearly a century ago Ward proposed that infections played a role in the etiology of childhood ALL [9]. Instead of cell targeting

0145-2126/$ see front matter. Crown Copyright 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2011.07.023

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Fig. 1. Schematic diagram of major activation (continuous lines) and suppression (dotted lines) regulatory pathways of a childs defensive response to microbial infections. Response times to infection are rapid (minutes to 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 aberrant immunological response to pre-natal infections, and especially post-natal infections that have a peak occurrence at 10 months old in an afuent 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 illnesses in infants and young children [12]. There is a riskespecially in neonatesthat serious infections (including common extracellular bacteria e.g., S. pneumoniae and H. inuenzae) may put the adaptive immune system and B-cells under proliferative stress (Fig. 1). The infective heat shock and lymphoid tissue recovery hypothesis (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 children, according to the following etiologic process: (a) hygienic conditions in infancy inhibit early immune priming, thus reducing the efcacy of the secondary immune response to later infections [13,14], (b) infectious fevers induce expression of heat shock proteins (HSP) and pro-inammatory T helper 1 (Th1) cell cytokines, both of which are conducive to cell survival and a hypermutatable state [15], (c) cytokine activation of the hypothalamicpituitaryadrenal axis, resulting in infection-related glucocorticoid release and transient involution of the thymus and other lymphoid organs, causes a decline in antitumor immunosurveillance and the maturation 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 premalignant precursor B-cells, and

(e) later release of Th2 cytokines augments a secondary and adaptive immune response, putting additional proliferative 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 threepart methodology (Fig. 2), and an extensive review of the associated literature, that in: Section 1 reconciles seemingly contradictory protective and promoting evidence concerning infectious exposure, 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 further explores the evidence for an infectious heat shock response and other factors identied 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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lymphoid recovery hypothesis to explain certain PBC-ALL characteristics, such as peak incidence at 25 years of age. 1. Infection paradox This section provides an explanation for the often contrary scientic evidence on the involvement and timing of infections in PBC-ALL etiology. Epidemiological studies and hypotheses identify a signicant but low risk of childhood leukemia from in utero infectious exposure during pregnancy [7,16]. McKinney et al. [17] found that, in British children, ALL was strongly associated with post-natal viral diseases (e.g., chicken pox, rubella, measles and inuenza) occurring within 6 months of birth, with the latent period to malignancy 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., inuenza). A later U.K. case control study [18] found that children aged 25 years diagnosed with ALL had an excess of clinically diagnosed (e.g., presence of fever) viral and bacterial 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 promotion of childhood ALL led Kinlen [19], Greaves [14], and Schmiegelow et al. [20] to postulate the population-mixing theory, the delayed rst exposure hypothesis, and the adrenal hypothesis, respectively; the latter is examined in the Discussion. Kinlens population-mixing theory proposed that workers moving to isolated communities expose immunologically nave infants to specic infections and a higher risk of ALL [19]. Greaves delayed rst exposure (or delayed infection) hypothesis is based on the necessity of an infectious challenge for the newborns nave immune system to mature and counter childhood ALL [14]. Accordingly, infants who experience a delayed exposure to infectious 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 signicant protective effect against ALL due to an early, elevated infectious exposure [7,21,22]. Yet, as discussed above, there is also seemingly contrary evidence that multiple or 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 identied from congenital syndromes and other 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 vulnerability to acute myeloid leukemia (AML), and particularly to PBC-ALL. Table 1 lists the relationship between childhood leukemia and the following conditions: Down Syndrome (DS); primary immunodeciency disorders (i.e., ataxiatelangiectasia and DiGeorge syndrome); chromosome fragility disorders (i.e., Bloom syndrome and Fanconi anemia); and ShwachmanDiamond syndrome and neurobromatosis (the latter arising from a tumorsuppressor gene mutation) [23]. The association of childhood ALL with lymphoid organ changes was reviewed to determine if a positive 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 signicantly 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 generally 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 administered 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 inammation and inhibits apoptosis [28]. Infections can be a concern in the chromosome fragility disorders Bloom syndrome and Fanconi anemia, although thymus abnormalities for either disorder are not prominent in the literature. Leukemia develops in about 1015% of both Bloom syndrome and Fanconi anemia 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 25 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 occurrence 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.

Table 1 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 (Mostly absent) Smaller (Absent) High dose only Abnormal non-thymic lymphoid tissue S, L Excessive rates of ALL with peak 25 y Excessive rates of non-PBC ALL leukemia T-ALL AML AML AML AML AML AML AML, JMML, T-ALL AML

Ataxiatelangiectasia [33,34] Breastfeeding (absence of) [3638] Bloom syndrome [29] Congenital heart defects [32] DiGeorge syndrome [35] Down syndrome [3942,48] Fanconi anemia [30] Infections (in utero and in infancy) [1618,59,61] Ionizing radiation [6,25,27] Neurobromatosis [23] ShwachmanDiamond syndrome [49]

BM, S, L BM BM, S, L BM, S, high dose only BM

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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There are several athymic medical conditions, including congenital 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 prole 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 ataxiatelangiectasia patients, who are also prone to developing non-hematologic and hematologic neoplasms, including T-cell ALL and AML [34]. The immunological abnormalities of DiGeorge syndrome individuals and their susceptibility to recurrent infections may be attributed to congenital underdevelopment of the thymus or, rarely, to its complete absence. B-cell maturation and the 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 syndrome who lack T-suppressor activity [35]. Childhood ALL is not prominent in these conditions, and therefore it appears that infections 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+ Tlymphocyte concentrations, and reduce the risk of respiratory tract infections 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 postnatal 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 conditions, DS children are the best studied. DS children are highly vulnerable to respiratory tract infections and an increased occurrence of thymic aberrations [39]. Marked (T- and B-) lymphocyte depletion has also been observed in the spleen and lymph glands of DS infants perhaps due to congenital factors [40]. It is well known that individuals with DS have a greatly elevated risk of childhood leukemia: the relative risks are about 1030 times higher than controls [39,41,42]. Neonates with DS exhibit a range of hematologic 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 chromosome 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-inammatory cytokine IFN- associated with stimulating the formation of common lymphoid progenitors [44,45]. IFN-inducible genes indicative of a viral infection are highly expressed in the hyperdiploid PBCALL 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-specic incidence rates [48]. A difference 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-Diamond syndrome [49]. These congenital syndromes display segmental symptoms of accelerated ageing, as does MDS,

a disease that can advance to AML, but not ALL. Similarly, thymectomy in congenital heart defect patients and the impaired thymic processes in ataxiatelangiectasia, DiGeorge syndrome and DS, prematurely age the immune system and downgrade the ability to countermand infections and tumors [32]. Nevertheless, the apparent lack of excessive rates of ALL in children with ataxiatelangiectasia, congenital heart defects, and DiGeorge syndrome implies that the absence or removal of an infants thymus is not enough in itself to induce PBC-ALL (Table 1). DS studies indicate an abnormal infective Th1 signaling response to an IFN-dependent immunosurveillance 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, malnutrition and 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 blood cells, overproduction of immature B-lymphocytes, and inhibition of B-cell deathgenetic hallmarks of PBC-ALL [5]. HSPs generated by the host upon invasion by viruses and bacteria (or the bacterias own HSPs) rapidly activate the innate immune system. This is followed by a hypothalamicpituitaryadrenal 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 genethe most common mechanism by which a neoplasm escapes apoptosisis weakly associated with leukemia. Only 5% of childhood ALL cases at diagnosis 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 constitutive expression of HSP90 is associated with the proliferation of 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 differentiation [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 inuence 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 Th1 pro-inammatory cytokines, including tumor necrosis factor- (TNF- ), interleukin-2 (IL-2) and IL-12 [56]. About two days after a heat shock response, Th1 cytokines stimulate increased glucocorticoid secretion during the post-stress recovery period, thereby causing transient involution of the thymus and limiting over-activity by the immune and inammatory pathways. Chronic (particularly bacterial) infections and heat shock result in cumulative stress-induced weakening of the glucocorticoid 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 ndings show that after sustained pre- or post-natal infections, there is cumulative degradation of lymphoid tissue requiring reconstitution.

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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-afnity 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 triggered by birth, with ten times fewer hematogones at 25 years old. Hematogones are especially prominent in children exhibiting a serious complication (e.g., acute thrombocytopenic purpura) 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, 01 year old [64]. Further evidence of arrested bone marrow maturation is provided by post-uterine CMV infections preceding the observation of hematogones of PBC-ALL-like cell types [65]. Therefore, 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 proliferation. A B-cell response is not limited to bacterial infections; for instance, the inuenza virus induces IFN-mediated B-cell activation and the production of antiviral antibodies [66]. In addition, respiratory syncytial virusthe principal etiologic agent of respiratory infections in infants and young childrenprovokes both a heat shock and Th2 response [67]. There is also evidence that dysregulation of the transforming growth factor- (TGF- ) pathway, a Th2 cytokine produced in response to infection and that accelerates thymic involution, is involved in the promotion of TELAML1-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 tissues. IL-7 serum levels are elevated after infections in general, and augment reconstitution of the thymus and spleen [69,70]. Perhaps related to DSs congenital vulnerability to childhood ALL, IL-7 levels are similarly raised in DS individuals aged 425 years old who 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 identied; 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 immature B-cells, which in turn promotes the transformation of 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 hypothalamicpituitaryadrenal axis. This theory maintains that infections raise glucocorticoid (e.g., cortisol) levels, which effectively 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 hypothesisnamely,

that the administration of glucocorticoid (either on its own or as part of an anti-inammatory, immunosuppressive and chemotherapeutic 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 rst of two seemingly contradictory mechanisms of the infection paradoxthat infections can provide both a protective and promotional mechanism in PBC-ALL etiology [14,1719]. 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 priming (more likely to occur in hygienic, socially isolated, and afuent societies) places greater reliance, when defending against infectious pathogens, on heat shock activation of the innate immune response and on a pro-inammatory state. However, later recurrent exposure to infectionsespecially in infancyhas an accumulative effect on activation of the hypothalamicpituitaryadrenal 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 on hematogones 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 25 years is more prominent in afuent societies as compared to populations with poor socio-economic conditions and high child mortality rates [7,10,20,74]. One factor that should be considered is that in less-afuent or developing countries, families are generally larger and live in closer quarters; this provides a parallel environment to the daycare centers in the developed world that immunologically prime young children and protect against childhood ALL [21,22]. Another factor likely inuencing the low ALL incidence rates in children of developing countries is their high rate of breastfeeding [75], which furthers thymic enlargement that improves the immunosurveillance of pre-leukemic cells and lessens the need for lymphoid tissue reconstitution. On the other hand, afuence and improved healthcare lead to more infants 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 exposure 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 casecontrol studies and found an inverse association between ALL and atopic allergies in children (e.g., asthma, eczema, and hay fever). Similarly, DS cases susceptible to ALL are associated with a signicant decit of asthma [41]. Allergies involve an excessive Th2 anti-inammatory response and class-switching to enhance the production of IgE antibodies. A possible explanation for the inverse relationship is that PBC-ALL is associated more strongly with a heat shock mediated Th1 response and lymphoid tissue reconstitution, as compared to a Th2 response. Further

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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 children do not have elevated levels of serum cortisol and Th1 pro-inammatory 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 infections 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 immunological (e.g., pro-B, pre-B) or cytogenetic variants, as suggested by high virus-mediated INF- levels associated with the hyperdiploid subtype [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 signicant aspect of the infective lymphoid recovery hypothesis is that it appears to explain the infection paradox and the prominence of the ALL peak incidence as being due to the shortening of the promotion/latent period by surviving multiple infections and an over-expressive lymphoid-recovery response. It is hoped that this 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 Children Research Institute, University of Toronto, Canada; and Patricia McKinney of University of Leeds, U.K. for their review of early drafts. The author also thanks Elizabeth Bond for careful proofreading of this manuscript. Funding source: None. Contributions: Richard B. Richardson is the sole author and contributor. Conict of interest: Richard B. Richardson has no conict to declare. References
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