Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening

Schafer, Daniel W.; Olsen, Marianne; Laehnemann, David; Stanulla, Martin; Slany, Robert K.; Schmiegelow, Kjeld; Borkhardt, Arndt; Fischer, Ute

doi:10.1182/blood-2017-09-808402

Cited by 83 publications

(106 citation statements)

References 24 publications

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“…The presence of clone-specific mutations in patient neonatal blood spots has demonstrated a prenatal origin of most B-cell precursor ALL cases, namely those with high-hyperdiploidy or ETV6-RUNX1-translocation. Recently, it was suggested that up to 5% of all newborns harbor translocation ETV6-RUNX1 (30). In combination with a constitutively aberrant immune system, it is possible that children who develop B-cell precursor ALL were unable to eliminate these preleukemic cells, thus allowing transformation to leukemia.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Inflammatory Markers Are Associated with Childhood B-cell Precursor Acute Lymphoblastic Leukemia

et al. 2018

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It has been proposed that children with acute lymphoblastic leukemia (ALL) are born with a dysregulated immune function that together with postnatal environmental exposures causes childhood ALL. Despite its importance for the understanding of ALL etiology, this hypothesis has been inadequately explored. In a population-based case-control study, we measured the concentrations of 10 cytokines and other inflammatory markers on neonatal dried blood spots from 178 children who at ages 1 to 9 years were diagnosed with B-cell precursor ALL and 178 matched controls. Through linkage with Danish nationwide registers, we also assessed whether neonatal inflammatory markers were associated with previously demonstrated risk factors for childhood ALL. Children who developed B-cell precursor ALL had significantly lower neonatal concentrations of IL8, soluble IL6 receptor (sIL6R) α, TGFβ1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP) and higher concentrations of IL6, IL17, and IL18 compared with matched controls. Concentrations of IL10 were below the detection level for both patients and controls. Birth order (IL18 and CRP), gestational age (sIL6Rα, TGFβ1, and CRP), and sex (sIL6Rα, IL8, and CRP), but not maternal age, infections during pregnancy, birth weight nor mode of delivery were significantly associated with the neonatal concentrations of inflammatory markers. Our findings support the hypothesis that children who later develop B-cell precursor ALL are born with a dysregulated immune function. Children who develop acute lymphoblastic leukemia are immunologically distinct at birth and could potentially react abnormally to infections in early childhood. .

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Section: Discussionmentioning

confidence: 99%

Neonatal Inflammatory Markers Are Associated with Childhood B-cell Precursor Acute Lymphoblastic Leukemia

et al. 2018

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“…As secondary alterations are needed for most subtypes, these first hits produce a preleukemic state. The secondary mutations only occur in a fraction of carriers [6][7][8][9]. There is convincing evidence that a significant percentage of these preleukemic lesions can arise prenatally and transform after postnatal secondary events occur [6][7][8][9][10][11][12] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Insights into the prenatal origin of childhood acute lymphoblastic leukemia

Hein

Borkhardt

Fischer

2020

Cancer Metastasis Rev

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Pediatric acute lymphoblastic leukemia (ALL) is defined by recurrent chromosomal aberrations including hyperdiploidy and chromosomal translocations. Many of these aberrations originate in utero and the cells transform in early childhood through acquired secondary mutations. In this review, we will discuss the most common prenatal lesions that can lead to childhood ALL, with a special emphasis on the most common translocation in childhood ALL, t(12;21), which results in the ETV6-RUNX1 gene fusion. The ETV6-RUNX1 fusion arises prenatally and at a 500-fold higher frequency than the corresponding ALL. Even though the findings regarding the frequency of ETV6-RUNX1 were originally challenged, newer studies have confirmed the higher frequency. The prenatal origin has also been proven for other gene fusions, including KMT2A, the translocations t(1;19) and t(9;22) leading to TCF3-PBX1 and BCR-ABL1, respectively, as well as high hyperdiploidy. For most of these aberrations, there is evidence for more frequent occurrence than the corresponding leukemia incidences. We will briefly discuss what is known about the cells of origin, the mechanisms of leukemic transformation through lack of immunosurveillance, and why only a part of the carriers develops ALL.

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“…A subsequent “second‐hit” occurring postnatally in a population of “preleukemia” cells would initiate the final steps for leukemia to develop and manifest clinically. Interesting, the ETV6‐RUNX1 fusion has been detected in up to 5% of healthy newborn blood samples, as an example of a relatively high proportion of children potentially harboring a “first‐hit” preleukemia clone 4 …”

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confidence: 99%

COVID‐19 and childhood acute lymphoblastic leukemia

Taub

Xavier

2020

Pediatric Blood & Cancer

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Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening

Abstract: 9. Zeidan AM, Sekeres MA, Garcia-Manero G, et al; MDS Clinical Research Consortium. Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides.

Cited by 83 publications

References 24 publications

Neonatal Inflammatory Markers Are Associated with Childhood B-cell Precursor Acute Lymphoblastic Leukemia

Neonatal Inflammatory Markers Are Associated with Childhood B-cell Precursor Acute Lymphoblastic Leukemia

Insights into the prenatal origin of childhood acute lymphoblastic leukemia

COVID‐19 and childhood acute lymphoblastic leukemia

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