In the absence of AML1-ETO (top scheme), the hematopoietic progenitor cells in the ICM will continue to express erythroid cell markers and will eventually become red blood cells. The chemical suppressors of AML1-ETO identified from the in vivo zebrafish screen may provide not only new insights into AML1-ETO-mediated hematopoietic differentiation but also new means to block AML1-ETO’s effects in the clinical settings.Įxpression of AML1-ETO in embryonic zebrafish reprograms hematopietic cell fateĪt 15-somite stage, erythroid cell markers such as gata1 are strongly expressed in the intermediate cell mass (ICM) of zebrafish embryos (indicated as a red stripe in the ventral side of the trunk). From this screen we have identified several classes of compounds that restored gata1 expression in the presence of AML1-ETO ( 3). Furthermore, to identify candidate small molecules that can reverse AML1-ETO’s effects and the mechanisms by which AML1-ETO reprograms hematopoietic cell fate, we conducted a chemical suppressor screen using zebrafish embryos. This fate switch is characterized by downregulation of gata1, suggesting suppression of erythropoiesis, and upregulation of mpo, indicating conversion into the granuocytic cell fate ( 2). We have shown that expressing AML1-ETO, an oncogene frequently associated with acute myelogenous leukemia, leads to a rapid and efficient cell fate switch in the posterior blood island of zebrafish embryos ( Fig. These synchronized pools of HPCs are useful for studying the signaling pathways that underlie or affect hematopoietic cell fate determination. On the other hand, the posterior blood island expresses gata1, and will differentiate into the erythroid cells ( 1). The anterior blood island expresses pu.1, and will give rise to the myeloid cells ( 1). Within the first day post-fertilization, zebrafish embryos develop two localized pools of hematopoietic progenitor cells (HPCs). Embryonic zebrafish is a powerful model to study hematopoietic cell fate. Many leukemic oncogenes, including AML1-ETO, contribute to leukemogenesis by modulating hematopoietic stem/progenitor cell differentiation.

Posterior blood island zebrafish