Genetic stability of human embryonic stem cells: A first-step toward the development of potential hESC-based systems for modeling childhood leukemia

Human ESCs provide an opportunity for modeling human-specific strategies to study the earliest events leading to normal hematopoietic specification versus leukemic transformation. Of interest, are the human childhood acute leukemias harboring specific fusion oncogenes such as MLL-AF4, TEL-AML1 or BCR-ABL wherein clinically significant manifestations arise in utero. The mechanisms of transformation are not amenable to analysis with patient samples and, many mouse models for pediatric leukemias have fallen short in illuminating the human disease because they do not recapitulate key aspects of the actual disease, suggesting that the mouse models are missing essential components of oncogenesis present in the human embryo. Prior to using hESCs as a tentative system for modeling leukemia, robust studies aimed at demonstrating their genetic stability are required; otherwise, cooperating mutations already present could prime hESCs susceptible to transformation. We performed an extensive molecular cytogenetic and cellular in vitro and in vivo analysis which reveals an overall genomic stability of HS181 and HS293 hESCs maintained long-term by mechanical dissociation in human feeders. Importantly, we show for the first time that the genetically stable HS181 hESC line differentiates into CD45+ hematopoietic cells and clonogenic hematopoietic progenitors. This data should encourage stem cell researchers to implement robust cytogenetic tools when assessing hESC genetic stability, in order to detect tiny but relevant biological functional or structural chromosome abnormalities and, paves the way for generating fusion oncogene-expressing transgenic hESCs as a human-specific system for studying the early in utero events leading to normal hematopoietic specification versus childhood leukemic transformation.