The neuronal homeobox transcription factor HMX3 is a crucial vulnerability factor in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia

Abstract

AbstractThe KMT2A::MLLT3 fusion protein causes acute myeloid leukemia (AML) by activating the oncogenic transcription factor MECOM. However,MECOMexpression occurs in only half of the KMT2A::MLLT3 cases. By integrating gene expression and enhancer activity data from patient cells, we identified neuronal homeobox transcription factorHMX3as cell fate determining factor inMECOM-negative KMT2A::MLLT3 AML.HMX3expression associated with younger age and KMT2A-rearranged leukemia in large AML cohorts (p<0.002).HMX3was not expressed in other major genetic risk groups and healthy blood cells. Transcriptomic analyses revealed thatHMX3drives cancer-associatedE2F,MYCand cell cycle gene programs. EctopicHMX3expression completely inhibited monocytic but not granulocytic colony formation of healthy CD34+adult cells. Silencing ofHMX3in KMT2A::MLLT3 AML cell lines and patient cells resulted in cell cycle arrest, monocytic differentiation, and apoptosis. Thus, HMX3 is a leukemia-specific vulnerability that enhances proliferation and blocks differentiation of MECOM-negative KMT2A::MLLT3 leukemia.