Molecular tracking of leukemogenesis in a triplet pregnancy

Abstract

The occurrence of childhood acute lymphoblastic leukemia (ALL) in 2 of 3 triplets provided a unique opportunity for the investigation of leukemogenesis and the natural history of ALL. The 2 leukemic triplets were monozygotic twins and shared an identical, acquired TEL-AML1 genomic fusion sequence indicative of a single-cell origin in utero in one fetus followed by dissemination of clonal progeny to the comonozygotic twin by intraplacental transfer. In accord with this interpretation, clonotypic TEL-AML1 fusion sequences could be amplified from the archived neonatal blood spots of the leukemic twins. The blood spot of the third, healthy, dizygotic triplet was also fusion gene positive in a single segment, though at age 3 years, his blood was found negative by sensitive polymerase chain reaction (PCR) screening for the genomic sequence and by reverse transcription-PCR. Leukemic cells in both twins had, in addition to TEL-AML1 fusion, a deletion of the normal, nonrearranged TEL allele. However, this genetic change was found by fluorescence in situ hybridization to be subclonal in both twins. Furthermore, mapping of the genomic boundaries of TEL deletions using microsatellite markers indicated that they were individually distinct in the twins and therefore must have arisen as independent and secondary events, probably after birth. These data support a multihit temporal model for the pathogenesis of the common form of childhood leukemia. IntroductionPediatric acute lymphoblastic leukemia (ALL) is a biologically and clinically diverse cancer. 1,2 The major subset (common ALL) has characteristics of B-cell precursors 3 ; the most frequent chromosomal and molecular genetic abnormalities are hyperdiploidy 4 and TEL-AML1 gene fusion, the latter generated by cryptic chromosomal translocation. 5,6 TEL-AML1 has transcriptional repressor function in model systems, 7,8 and it is assumed that this chimeric protein plays a key role in leukemogenesis. Until recently, however, it was unclear whether this fusion represents an initiating event in leukemogenesis and, if it does, when it occurs and what other complementary or secondary genetic changes are necessary. Studies of monozygotic twins with TEL-AML1-positive ALL have provided compelling evidence that this fusion gene can arise in utero, 9,10 validated by the finding of clonotypic TEL-AML1 fusion sequences in the neonatal blood spots (Guthrie cards) from singleton children with ALL. 11 Taken together with the concordance rate of ALL in identical twins (approximately 5%), 9 these data then suggested a multistep model for the pathogenesis of ALL involving in utero initiation and at least one necessary postnatal secondary or promotional event. 12 Deletions of the normal, nonrearranged TEL allele are frequent in patients with ALL with TEL-AML1 fusion 13,14 suggesting that this could represent a common, though not exclusive, secondary event.We describe here an unusual set of triplets in whom a monozygotic pair had ALL and their dizygotic twin brother was healthy. Leukemic cells of...

Non‐identical monozygotic twins, intermediate twin types, zygosity testing, and the non‐random nature of monozygotic twinning: A review

“…It has therefore been recommended that all same-sex twins should have a follow-up TSH screen at 14 days. Transfusion of bone marrow hematopoietic precursor cells has been implicated in childhood acute lymphoblastic leukemia in MZ twins [Maia et al, 2001;Mori et al, 2002]. There is modest concordance (level of 5%) in MZ twins, with protracted latency in some cases.…”

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

“…Concordance of disease then arises via spread of clonal progeny from one twin, in which the translocation arises, to the other prenatally via vascular anastomoses within a monochorionic placenta . The identification of clonotypic TEL-AML1 genomic sequences in neonatal blood spots (Wiemels et al, 1999a;Maia et al, 2001;Hjalgrim et al, 2002) provides direct evidence for the existence of the fusion gene at birth. These data are endorsed by the detection of putative preleukaemic B-lineage cells in normal cord blood that harbour TEL/AML1 translocations (Mori et al, 2002) (see Figure 3).…”

“…There might not be an exclusive second genetic 'hit', but at diagnosis most cases of ALL with TEL-AML1 fusions have deletion of the nonrearranged or normal TEL allele. Deletions are subclonal to TEL-AML1 fusions (Romana et al, 1996) and are distinct in their genomic boundaries in twins (Maia et al, 2001), and in relapse versus diagnostic samples from the same individuals . TEL deletions are therefore likely to be postnatal secondary events, albeit a common and integral component of the molecular pathogenesis of cALL .…”

In Utero Pesticides Exposure and Generation of Acute Myeloid Leukemia Associated Translocation (8; 21)

“…[2][3][4] Indeed, the presence of chromosomal fusion and sequence rearrangements in archived neonatal heel-prick spots of children who later developed leukemia also supports the theory of its prenatal origin. [2][3][4] Translocation (8; 21) is one of the most common chromosomal translocations; its frequency ranged from 20% 5 to 30% 6 in AML cases. The translocation results in fusion of 5` end of exon 2 of the ETO gene on chromosome 8 with 3` end of exon 5 of AML1 gene on chromosome 21, producing a novel chimeric gene, AML1-ETO.…”