Targeting the fetal transcriptional landscape of pediatric AML

Acute myeloid leukemia (AML) is caused by an accumulation of genetic aberrations. Therapeutic targeting of causative oncogenic proteins has remained widely unsuccessful. Essentially, the fetal origin of AML is one of the most distinct unifying features of this heterogeneous group of disorder. We created a hematopoietic atlas to identify fetal stage specific genes and transcripts that are expressed in pediatric AML and in fetal HSCs but are absent from healthy differentiated progenies and adult HSCs. Here, we utilized the CRISPR/Cas9 system to perform pooled library screens on AML cell lines of different subtypes murine fetal HSC based preleukemic model and patient derived xenografts (PDX). We were able to identify novel genes such as the proto-oncogene MYBL2. We further aim to validate these gene candidates and explore their role in leukemogenesis. This work will lay the foundation for developing novel targeted cancer specific therapies, based on this yet unrecognized therapeutic window.