ETV6-RUNX1+ Acute Lymphoblastic Leukaemia in Identical Twins
Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes;
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Anthony M. Ford and Mel Greaves
Abstract
Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1). The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells. Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia. Keywords
Leukemia • TEL-AML1 • ETV6-RUNX1 • RUNX • Twins • In utero • Infection
A.M. Ford, Ph.D. (*) • M. Greaves, FRS Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 Y. Groner et al. (eds.), RUNX Proteins in Development and Cancer, Advances in Experimental Medicine and Biology 962, DOI 10.1007/978-981-10-3233-2_14
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14.1 Introduction Acute Lymphoblastic Leukaemia (ALL), a disease of the bone marrow, accounts for about 30 % of cancer diagnosed in children under the age of 15 years (Dickinson 2005). The disease is biologically and clinically diverse with distinctive subtypes, each characterized by an association between age at presentation of overt leukaemia and various recurrent genetic alterations. Multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance (reviewed in (Rowley et al. 2015)). The most common chromosome translocation observed in ALL is the t(12;21) (Golub et al. 1995; Romana et al. 1995). The translocation results in an in-frame fusion between the first five exons of ETV6 and almost the entire coding region of RUNX1; bringing together the PTD and repression domains of ETV6 and the DNA binding (RHD), repression and transactivation domains of RUNX1 (Golub et al. 1995; Romana et al. 1995), Fig. 14.1. Both RUNX1 and ETV6 are important transcription factors required for normal haematopoiesis (Okuda et al. 1996; Wang et al. 1996). Although cryptic
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