Possible role of pandemic AH1N1 swine flu virus in a childhood leukemia cluster

Cazzaniga, Giovanni; Bisanti, Luigi; Randi, Giorgia; Deandrea, Silvia; Bungaro, Silvia; Pregliasco, F.; Perotti, Daniela; Spreafico, Filippo; Masera, Giuseppe; Valsecchi, Maria Grazia; Biondi, Andrea; Greaves, Mel

doi:10.1038/leu.2017.127

Cited by 24 publications

(31 citation statements)

References 15 publications

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“…All seven cases had been infected with endemic AH1N1 swine flu virus during the epidemic that preceded the ALL cluster by three to six months. The infection frequency in children in Milan during the same period was relatively high, at around one third, but this still indicated the link with cases was significantly different from expected (p = 0.01) 121 . Six of the seven cases were first born and none attended day care in the first year of life.…”

Section: Clusters Of Allmentioning

confidence: 72%

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A causal mechanism for childhood acute lymphoblastic leukaemia

2018

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In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1) ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.

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Section: Clusters Of Allmentioning

confidence: 72%

“…A significant space-time cluster of BCP-ALL in Milan has recently been recorded 121 . Seven cases were diagnosed in a four week period; four of these lived within one small residential area and three of these four attended a single school.…”

Section: Clusters Of Allmentioning

confidence: 99%

A causal mechanism for childhood acute lymphoblastic leukaemia

2018

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“…5 It is possible to test and deconvolute these two scenarios. Cases of ALL diagnosed over 2020 and beyond could be screened for viral antibodies in blood plasma (as for AH1N1 4 Studies along these lines have been initiated in some European countries. Hopefully, these will be expanded and include international collaboration.…”

Section: Covid-19 and Childhood Acute Lymphoblastic Leukemiamentioning

confidence: 99%

“…A report from the UK documented that spikes in ALL incidence followed some months after epidemics of seasonal flu 3 . During the 2009/2010 AH1N1 swine flu pandemic, a significant space/time cluster of virus‐associated cases was detected in Milan around 2‐3 months after the peak infection rate in Italy 4 . The timing of these associations indicates that any causal involvement of the viral infection would have to be as a proximal or promotional trigger.…”

mentioning

confidence: 99%

COVID‐19 and childhood acute lymphoblastic leukemia

Greaves

2020

Pediatric Blood & Cancer

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“…However, there are numerous reports of pB-ALL space-time clusters associated with specific pathogens: streptococcal fever for 8 same-school patients in the Niles cluster, 15 adenovirus for 13 patients in the Fallon cluster, 16 and influenza A H1N1 swine flu virus for 7 patients in the Milan cluster. 17 Furthermore, a study in the United Kingdom observed peaks of pB-ALL ;6 months after seasonal influenza epidemics. 18 Notably, concomitant with rising levels of hygiene standards, the incidence of pB-ALL has increased in developed societies.…”

Section: Introductionmentioning

confidence: 99%

An intact gut microbiome protects genetically predisposed mice against leukemia

Vicente-Dueñas

Janssen

Oldenburg

et al. 2020

Blood

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The majority of childhood leukemias are precursor B cell-acute lymphoblastic leukemias (pB-ALL) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1-5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. While infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, employing murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice even in the absence of infectious stimuli and independent of T-cells. Using V4 and full-length 16S rRNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3,983 amplicon sequence variants (ASVs) as proxies for bacterial species. Transplantation of either wild type (WT) or Pax5+/- hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor-genotype-specific manner. Gas chromatography-mass spectrometric (GC-MS) analyses of sera from WT and Pax5+/- mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.

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Possible role of pandemic AH1N1 swine flu virus in a childhood leukemia cluster

Cited by 24 publications

References 15 publications

A causal mechanism for childhood acute lymphoblastic leukaemia

A causal mechanism for childhood acute lymphoblastic leukaemia

COVID‐19 and childhood acute lymphoblastic leukemia

An intact gut microbiome protects genetically predisposed mice against leukemia

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