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The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_primary_HMX3_KMT2A-MLLT3_AML]

GSE242961 Homo sapiens Expression profiling by high throughput sequencing 4 samples Submitted 2024/12/13 Platform GPL18573
Summary
The KMT2A::MLLT3 fusion protein causes acute myeloid leukemia (AML) by activating the oncogenic transcription factor MECOM. However, MECOM expression occurs only in half of the cases. By integrating gene expression and enhancer activity data from patient cells, we identified neuronal homeobox transcription factor HMX3 as cell fate determining factor in MECOM-negative KMT2A::MLLT3 AML. HMX3 expression associated with younger age and KMT2A-rearranged leukemia in large AML cohorts (p<0.002). It was absent in other major genetic risk groups and healthy blood cells. Transcriptomic analyses revealed that HMX3 drives cancer-associated E2F, MYC, and cell cycle gene programs. Ectopic HMX3 expression completely inhibited monocytic but not granulocytic colony formation of healthy CD34+ cord blood cells. Its silencing in 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.
Published in
HMX3 is a critical vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia
Arza-Apalategi S, Heuts BMH, Bergevoet SM et al. · Leukemia 2025 · PMID 39633068 · doi:10.1038/s41375-024-02485-3
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Also filed as BioProject PRJNA1015623 and SRA study SRP459919. Searching any of these in the dataset finder brings you back here.

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