Insights into the prenatal origin of childhood acute lymphoblastic leukemia

Abstract

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.

Keywords: ALL; Fusion genes; Preleukemia; Prenatal origin.

Fig. 1

Age distribution and major subtypes of ALL. a Age distribution of ALL and AML in the USA from 1975 to 2016. Cases per 100,000 are shown. ALL has a clear peak at ages 1–4 and 5–9, whereas AML rates rise with age. b Major subtypes of ALL divided by age groups. The KMT2A-AFF1 fusion is very prevalent in infants, ETV6-RUNX1 and high hyperdiploidy (HD) dominate childhood ALL, and BCR-ABL1 is the most prevalent aberration in adults. Data for (a) taken from [1], data from (b) taken from [3]

Fig. 2

Timeline of ALL development. The initiating lesions (green) occur in utero and lead to a state of preleukemia after birth. Exposure to infection leads to a dysregulated immune response in a small fraction (about 0.2–1%) of preleukemic children. Most preleukemic children remain healthy [6, 7]. The children develop ALL by acquiring secondary mutations, eventually leading to clonal expansion. In the case of KMT2A rearrangements (KMT2A-r, right), it is not completely clear whether the KMT2A-r are sufficient for ALL development (right dashed arrow). It is also possible that the KMT2A-r directly trigger secondary mutations (central dashed arrow). One case of a healthy KMT2A-r carrier has been reported [13], leading to the possibility of a preleukemic state for those cases (left dashed arrow). The given median ages of ALL onset are 2–5 years of age for B cell precursor subtypes (BCP, left) and < 1 year of age for pro-B cell subtype (pro-B, right)

Fig. 3

Model of the impact of NK cells on ALL development. a A prenatal preleukemic hit emerges in utero (red) and an expanded clone is present at birth. According to this model, interaction with NK cells plays a key role in leukemia development. HLA-C2 receptors (lavender) pose an elevated risk for ALL and can also interact with activating KIRs, e.g., KIR2DS1 [82]. An elevated number of activating KIRs (red), especially from the telomeric B cluster also pose a risk (right), whereas HLA-C1 (blue) and more inhibitory KIRs, i.e., the A-haplotype (green) seems to protect against ALL (left). b Scheme of NK cell killing efficiency and risk of developing ALL. NK cells with more inhibitory KIRs (green) have a higher killing efficiency and confer a lower risk of ALL; NK cells with more activating KIRs (red) have a lower killing efficiency and confer a higher risk of ALL