Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

Abstract

Childhood T-cell precursor acute lymphoblastic leukemia (TCP ALL) is an aggressive disease with a presumably short latency that differs in many biologic respects from B-cell precursor (BCP) ALL. We therefore addressed the issue of in utero origin of this particular type of leukemia by tracing oncogenic mutations and clone-specific molecular markers back to birth. These markers included various first-and second-hit genetic alterations (TCRD-LMO2 breakpoint regions, n ‫؍‬ 2; TAL1 deletions, n ‫؍‬ 3; Notch1 mutations, n ‫؍‬ 1) and nononcogenic T-cell receptor rearrangements (n ‫؍‬ 13) that were derived from leukemias of 16 children who were 1.5 to 11.2 years old at diagnosis of leukemia. Despite highly sensitive polymerase chain reaction (PCR) approaches (1 cell with a specific marker among 100 000 normal cells), we identified the leukemic clone in the neonatal blood spots in only 1 young child. These data suggest that in contrast to BCP ALL most TCP ALL cases are initiated after birth. (Blood. 2007;110:3036-3038)

Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2–harboring clones as main relapse-driving force in childhood ALL

“…8 In line with various other leukemia clone-specific markers, we also confirmed that at least in cases with a major P2RY8-CRLF2-positive clone the fusion is already present at birth. [16][17][18][24][25][26][27] Apart from that, however, P2RY8-CRLF2-positive clones do not seem to have any particular proliferative or selective advantage and therefore also not the necessary fitness to evolve into a disease-relevant relapse clone. This view is supported by experiments showing in various model systems that neither fusion nor CRLF2 overexpression alone is sufficient to transform cells without the concomitant expression of certain activating mutations, such as those affecting the JAK2, CRLF2, or IL7R genes.…”

“…DNA was extracted from one-third of a neonatal blood spot (Guthrie card), essentially as described previously with minor variations (see supplemental Figure 5). [16][17][18] From cases with the previously published breakpoints, the genomic fusion was determined in whole genome-amplified Guthrie card DNA by TaqMan qRT-PCR as described in "Quantification of genomic P2RY8-CRLF2." For the case with the newly identified breakpoint, a patientspecific nested 2-round PCR was established using a standard curve (10-log dilutions) from the respective diagnostic leukemia DNA.…”

Low numbers of pre-leukemic fusion genes are frequently present in umbilical cord blood without affecting DNA damage response

“…The development of pediatric ALL is a multistep process driven by the accumulation of two types of genetic abnormalities, (i) 1 st hit, often a chromosomal translocation generating a pre-leukemic fusion gene (PFG), and (ii) 2 nd hit, often point mutations, deletions, duplications. Several data, including studies in identical twins and with neonatal spots (Guthrie cards) have suggested that the initiation of childhood ALL-associated chromosomal translocations may arise in utero during fetal hematopoiesis [3–9]. The resultant fusion gene product with a novel activity, different from the activities of individual partner genes, produces a persistent, but covert pre-leukemic clone [10–12].…”

Etiology of common childhood acute lymphoblastic leukemia: the adrenal hypothesis

“…Less is known of the preleukemic (subclinical) phase for other subsets of childhood ALL, but Guthrie card and twin/triplet studies indicate that t(1;19)(q23;p13)[E2A-PBX1] translocation-positive cases and T-lineage ALL in general are initiated postnatally. [19][20][21] GCs are among the most important and effective inducers of apoptosis in normal and malignant lymphoblasts both in vitro and in vivo. 22,23 As monotherapy, both prednisolone and prednisone, which after absorption rapidly is converted to prednisolone, can induce morphological remission.…”