Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia

Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor- B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL- AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, we establish the lineal relationship between these cancer- propagating cells and the preleukemic cell in which the TEL- AML1 fusion first arises or has functional impact. Analysis of TEL- AML1- transduced cord blood cells suggests that TEL- AML1 functions as a first- hit mutation by endowing this preleukemic cell with altered self- renewal and survival properties.