RUNX1-ETO translocations must proceed CSF3R mutations to promote acute myeloid leukemia development

Acute myeloid leukemia (AML) is a deadly blood cancer character by an overproduction of immature myeloid cells. AML has a high degree of genetic diversity, and the presence or absence of particular genetic alterations can greatly impact prognosis. In AML, patients with CSF3R mutations exhibit high relapse rates and poor overall survival. A recent study found that 90.5% of patients with CSF3R mutations had cooccurring RUNX1-ETO (8;21), CBFB-MYH11, or CEBPA mutations7. The RUNX1-ETO and CBFB-MYH11 translocations disrupt the core binding factor complex, an important transcriptional regulator in myeloid development. In this study, we evaluated how RUNX1-ETO modifies CSF3RT618I-driven transcriptional changes to promote the production of myeloblasts in AML. We find that RUNX1-ETO accelerates CSF3R-driven oncogenesis both in vitro and in vivo. Furthermore, RUNX1-ETO impairs the ability of CSF3R to drive myeloid differentiation associated transcriptional programs resulting in the production of immature myeloblasts which characterize this disease. Overall design: RNA-Seq of HoxB cells expressing RUNX1-ETO and CSF3R-T618I in an order-dependent manner.