By David P. Steensma, MD

2008-12-08

Human twins — especially the identical, monozygotic variety — have long been objects of special curiosity and fascination. Twins have been irresistible study subjects for parents with an inclination to dress them identically, and have also attracted others with more serious experimental goals. It was Francis Galton, Charles Darwin’s cousin and founder of the pseudoscience of eugenics, who first proposed in the 1870s that careful comparison of identical and fraternal twins might provide answers to age-old questions of “nature versus nurture.” Although Galton’s eugenics has been marginalized, or frankly reviled, in many countries since its misuse as a tool of oppression before and during the Second World War, Darwin’s cousin was spot-on about twin studies: They have indeed yielded many important biological insights, including a better understanding of leukemia evolution.

In yesterday’s Plenary Scientific Session, Dr. Lyndal Kearney of The Institute of Cancer Research in the United Kingdom (linked to the Royal Marsden Hospital, a London cancer specialty hospital) discussed new insights into leukemia genetics gained from analysis of blood samples from monozygotic twins with concordant acute lymphoblastic leukemia (ALL) (abstract #2). Dr. Caroline Bateman (the lead author), Dr. Kearney, and their colleagues used high resolution single nucleotide polymorphism (SNP) arrays to analyze gene copy number variation within five twin pairs who shared pre-B-cell ALL associated with ETV6-RUNX1 fusion (formerly termed TEL-AML1, the product of an oncogene and a core binding factor subunit). The investigators were able to demonstrate that the twins, who share the same ETV6-RUNX1 fusion gene, were discordant for other leukemia-associated mutations, including PAX5, ETV6, and other genes regulating B-cell differentiation or cell cycle. This finding strongly suggests that ETV6-RUNX1, which results from the t(12;21) that is the most common chromosomal translocation in ALL, is the initiating event in the development of ALL, while the other important “driver” and incidental “passenger” mutations identified by SNP arrays are secondary and post-natal — an observation that generated great excitement among the reviewers of the abstract.

The senior author on this study was Professor Mel Greaves, who has published a number of influential papers describing molecular studies in twins with leukemia over the past 15 years. “We’ve reported in the past that as many as 1 percent of cord blood samples from apparently healthy neonates have a functional ETV6-RUNX1 fusion gene in B-lineage cells, but few of these infants go on to develop ALL. My interest is in understanding the critical secondary events in leukemogenesis, in order to gain additional insight into what causes or promotes them, such as a disordered immune response,” reported Dr. Greaves. His work has also demonstrated that similar mutant clones of leukemic cells are usually present in both twins who share a double tragedy of mutual childhood ALL. These mutations are acquired in utero, rather than germline. The idea of parasitization of cancer cells from one twin to another in utero may seem deeply troubling, though it is illustrative of neoplastic cells’ ability to exploit ancient evolutionary adaptations — a “Darwinian medicine” concept expanded in Greaves’ lucid and insightful book “Cancer: The Evolutionary Legacy,” published in 2000.

Dr. Janet Davison Rowley, of the University of Chicago, who will introduce this study, has built a stellar career by identifying acquired chromosomal abnormalities in cancer and their molecular consequences. For instance, she was the first to discover a recurrent chromosome translocation in acute leukemia in the early 1970s: the t(8;21) translocation, which involves the same RUNX1 gene that is fused with ETV6 in t(12;21). “The impressive new data in the paper presented by Dr. Kearney give us important new insights into the sequential acquisition of genetic lesions in cancer,” stated Dr. Rowley. “This work is part of an ongoing effort to identify what are the secondary changes, genetic or epigenetic, required to produce a fully leukemic cell. We want to know when these changes occur prenatally or after birth and whether they are universal — are they the same in each twin pair, or similar in different twin pairs? The study also highlighted just how much detailed study of abnormal chromosomes continues to tell us about human leukemia.”

Dr. Steensma indicated no relevant conflicts of interest.

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