MECOM – acute myeloid leukemia

The MECOM locus, encoding the EVI1 transcription factor, is recurrently involved in chromosomal rearrangements and overexpression in acute myeloid leukemia ([PMID:12393383]). EVI1 maps to chromosome 3q26.2, and rearrangements at this locus, including inv(3)(q21q26) and t(3;3)(q21;q26), lead to ectopic MECOM activation and an aggressive AML phenotype. Overexpression of the EVI1 isoform, as distinct from MDS1-EVI1, is associated with adverse cytogenetics and poor survival, independent of other molecular alterations ([PMID:12393383]).

Somatic MECOM activation in AML is driven by recurrent 3q26 aberrations and fusion events. In a cohort of seven patients with inv(3)(q21q26) or t(3;3)(q21;q26), only one case lacked EVI1 overexpression, underscoring its central role in leukemogenesis ([PMID:15138998]). Cryptic rearrangements producing H2AFY–MECOM fusions have been validated by transcriptome sequencing in elderly AML patients, confirming novel partner genes in MECOM-driven AML ([PMID:29666008]). Rare RUNX1–MECOM fusion transcripts presenting with marked eosinophilia further illustrate the diverse spectrum of MECOM rearrangements ([PMID:25379409]).

Functional assays demonstrate that MECOM overexpression promotes self-renewal and transformation of hematopoietic progenitors. In mouse bone marrow transplantation models, coexpression of AML1-D171N and EVI1 induces MDS/AML with short latency and phenocopies human disease features, including hepatosplenomegaly and dysplasia ([PMID:18192504]). At the molecular level, MECOM transcription is regulated by RUNX1 and ELK1 binding to its minimal promoter, and post-translational modifications such as serine phosphorylation modulate DNA binding and transforming ability, aligning with human AML phenotypes ([PMID:22689058]).

Clinically, high EVI1 expression defines a distinct high-risk subgroup of de novo AML. Patients in the intermediate-risk karyotype group with elevated EVI1 have significantly shorter overall and event-free survival, establishing MECOM as an independent prognostic biomarker ([PMID:12393383]). Integration of MECOM status into diagnostic panels can refine risk stratification and guide therapeutic decisions, particularly in the context of targeted agents.

References

• Genes, chromosomes & cancer • 2004 • Molecular heterogeneity in AML/MDS patients with 3q21q26 rearrangements. PMID:15138998
• Blood • 2003 • High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. PMID:12393383
• Cancer genetics • 2018 • H2AFY is a novel fusion partner of MECOM in acute myeloid leukemia. PMID:29666008
• Leukemia research reports • 2014 • An unusual case of splenomegaly and increased lactate dehydrogenase heralding acute myeloid leukemia with eosinophilia and RUNX1-MECOM fusion transcripts. PMID:25379409
• Blood • 2008 • AML1 mutations induced MDS and MDS/AML in a mouse BMT model. PMID:18192504
• Oncogene • 2013 • Functional characterization of the promoter region of the human EVI1 gene in acute myeloid leukemia: RUNX1 and ELK1 directly regulate its transcription. PMID:22689058

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