Deciphering the complex, deregulated transcription network in the development of leukemia in children with Down syndrome

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Structural and numerical aberrations of chromosome 21 are the most common cytogenetic changes in pediatric acute leukemias, whereas children with Down syndrome (DS, trisomy 21) have an approximately 500-fold increased risk to develop myeloid leukemia (ML-DS). About 95% of children with ML-DS carry mutations in the hematopoietic transcription factor GATA1, resulting in the exclusive expression of a truncated protein (GATA1s).In the running project, we elucidated the as yet unknown molecular role of pathognomonic GATA1s mutation in the process of leukemia. By complex functional studies in human primary blasts and a newly generated mouse model for ML-DS, we were able to discover that GATA1s fails to control the increased proliferation rate of fetal megakaryocytic and eosinophil progenitor cells. At the same time the function of GATA1 to induce eosinophil and megakaryocytic genes remains intact. The increased proliferation rate seems to be mainly induced by IGF2 via activation of the E2F-cell cycle regulators. , IGF2 is secreted by the fetal liver. Mechanistically, we showed that the GATA1s mutation impairs the protein interactions with E2F1. As the growth of fetal megakaryocytic progenitor cells but not of their ostensibly similar adult counterparts is dependent on IGF2, our study elucidates important yet unknown differences between fetal and adult hematopoiesis. Furthermore, our study explains the fetal origin of ML-DS. Despite these new insights two questions remain unanswered, which we will address in the follow-up project. First, what intrinsic genetic network determines the dependency of fetal hematopoietic progenitor cells on IGF2 and the sensitivity to the GATA1s mutation? Second, why does GATA1s induce megakaryocytic, but not erythroid genes? Answering these questions is essential to develop targeted therapeutic options for infant leukemias.