Natural history and cell of origin of TCF3-ZNF384 and PTPN11 mutations in monozygotic twins with concordant BCP-ALL

Abstract

To the editor: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood cancer and is molecularly heterogeneous. Identical twins with concordant BCP-ALL have provided a unique and tractable model to delineate the natural history and clonal evolution of the disease. Such studies have led to the 2-hit model for pediatric BCP-ALL, elucidated by Greaves, which provides unambiguous evidence that an initiating alteration, often occurring in utero, generates a preleukemic clone, which eventually gives rise to an overt leukemia upon acquisition of secondary cooperating mutations. Importantly, genome-wide sequencing has revealed a strikingly silent mutational landscape in childhood BCP-ALL, further indicative of a developmental cancer of prenatal origin, with a short window of time to accumulate molecular alterations.