The transcription factor HOXA9 induces expression of the chromatin modifier SMYD3 to drive leukemogenesis

Fusion oncogene MLL-AF9 initiates AML via downstream targets such as HOXA9. Drivers in the complicated settings of advanced AML, however, remain to be incompletely elucidated. Any factors to incur upregulation of the effector HOXA9 predictably aggravate the effect of DOT1L-mediated H3K79 methylation on HOXA9 expression in MLL-AF9-driven AML. In the present study, we identified that SET and MYND domain-containing protein 3 (SMYD3) was overexpressed in AML and predicted a poor prognosis for AML patients. Given that H3K4me3 typically activates the transcription of oncogenes, we hypothesized that SMYD3-catalyzed H3K4me3 may directly increase HOXA9 transcription, offering an additional regulation layer to HOXA9 gene transcription activation in MLL-AF9 AML. We tested this hypothesis and unveiled that SMYD3 is responsible for mediating H3K4me3 enrichment and for independently activating HOXA9 transcription. Transcription factor HOXA9 in turn bound to the promoter region of SMYD3 and enhanced its transcription. The resultant vicious circle of SMYD3-H3K4me3-HOXA9 exacerbated proliferation and blocked differentiation in both AML cell lines and primary cells fractionated from patients with AML. Combinational disruption of this loop and DOT1L inhibition led to enhanced anti-leukemia activity against MLL-AF9 AML in vitro and in vivo. In conclusion, our findings may advocate the current understanding regarding the underlying mechanism and offer SMYD3 as a promising intervention target to override the complicated settings in advanced AML.