Leukemia in twins: lessons in natural history

Abstract

Identical infant twins with concordant leukemia were first described in 1882, and since that time many such pairs of infants and older children have been described. It has long been recognized that this situation offers a unique opportunity to identify aspects of the developmental timing, natural history, and molecular genetics of pediatric leukemia in general. We reviewed both the older literature and more recent molecular biologic studies that have uncovered the basis of concordance of leukemia. Molecular markers of clonality, including unique, genomic fusion gene sequences, have provided unequivocal evidence that twin pairs of leukemia have a common clonal origin. The only plausible basis for this, first suggested more than 40 years ago, is that following initiation of leukemia in one twin fetus, clonal progeny spread to the co-twin via vascular anastomoses within a single, monochorionic placenta. This explanation has been endorsed by the identification of clonotypic gene fusion sequences in archived neonatal blood spots of individuals who subsequently developed leukemia. These analyses of twin leukemias have thrown considerable light on the natural history of disease.They reveal a frequent prenatal origin and an early or initiating role for chromosome translocations. Further, they provide evidence for a variable and often protracted latency and the need, in childhood acute lymphoblastic leukemia (ALL)/acute myeloblastic leukemia (AML), for further postnatal exposures and/or genetic events to produce clinical disease. We argue that these insights provide a very useful framework for attempts to understand etiologic mechanisms. IntroductionAround 3 to 4 per 1000 live births produce a clone of 2 genetically identical twins. These twins are monozygotic, being derived from a single fertilized ovum followed by splitting of the early embryo. In contrast, fraternal or nonidentical twins are simultaneously derived from independent, fertilized ova and have the same genetic diversity as non-twinned siblings. The common genetic heritage of monozygotic twins is instantly recognizable in their striking similarity of appearance, and, principally for this reason, they have been singled out in almost all human cultures, historical and contemporary, as deserving of special attention. This unique status is reflected in a rich mythology, literature, and art. 1,2 In some respects, this interest has been relatively trivial, focusing, as did Shakespeare, on the comic potential of mistaken identity. But twins also raise more fundamental philosophical and ethical issues. They challenge our precepts of identity, individuality, and fate. Recently, their "natural" origins have been used, in our view erroneously, to legitimize the prospect of human reproductive cloning. Their common inheritance also raises questions of importance to medicine and, in particular, provides an opportunity to explore vulnerability to disease. Not surprisingly, therefore, twins have been much used, and occasionally abused, in biomedical research.In 1875, Fran...

A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology

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Childhood and maternal infections and risk of acute leukaemia in children with Down syndrome: a report from the Children's Oncology Group

“…Analyses of the association between acute leukemia and child infections were restricted to children over 1 year of age at diagnosis, or the corresponding reference date for controls, to ensure that there was an adequate window for exposure to infections. In addition, evidence indicates that leukaemia in the first year of life probably develops in utero, and thus postnatal exposures may not play an aetiologic role (Greaves et al, 2003). Six (4%) cases (one ALL and five AML) and 21 (12%) controls were younger than 1 year of age.…”

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