Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

Abstract

T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7⁺/CD34⁺ leukemic cell transplantations. Here we investigated the genetic characteristics of CD7⁺/CD34⁺ and CD7⁺/CD34⁻ cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7⁺/CD34⁺ or CD7⁺/CD34⁻ T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7⁺/CD34⁺ or CD7⁺/CD34⁻ cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments.