High MECOM protein levels confer adverse prognosis in acute myeloid leukemia independent of Chromosome 3 abnormalities

MDS1 and EVI1 Complex locus (MECOM) gene rearrangements (MECOM-R) occur in ~2% of AML, with EVI1 protein overexpression causing aggressive disease. EVI1 overexpression in non-MECOM-R cases also occurs and is prognostically adverse, suggesting that EVI1 protein overexpression could induce similar biological programs without MECOM-R. We measured MECOM protein in 810 untreated AML cases (MECOM-R = 2%), observing low protein in 86% and high expression in 14%. High protein was equally prognostically adverse with MECOM-R, other Chromosome 3 (Chr3) abnormalities (Chr3-abn), or Chr3-wild-type (WT). Despite high protein expression co-associating with known adverse features, high MECOM was independently prognostic in CoxPH models. High MECOM protein overrides the benefit of mutant CEBPα protein. Protein-protein correlations and networks were similar between MECOM-R, Chr3-WT-high and Chr3-abn-High, with common activated pathways, but also distinct ones. Chr3-WT-high cases also overexpressed MDS1/EVI1 and expressed proteins favoring epigenetic deregulation, explaining some observed differences. Collectively, we showed that elevated MECOM protein levels in non-MECOM-R cases are equally adverse to MECOM-R cases, and share similar biological programs, suggesting that therapies targeting MECOM-related proteins may be efficacious beyond those with MECOM-R. Clinically measuring MECOM protein levels could be a useful strategy to stratify patients and guide therapy recommendations.