New research, presented at the American Society of Hematology (ASH) 2025 Congress, has identified a previously unrecognised mechanism controlling MEF2C stability in acute myeloid leukaemia, revealing a paralog dependency that sustains malignant cell growth and may represent a novel therapeutic vulnerability.
Paralog Dependency Underpins MEF2C Stability
Acute myeloid leukaemia is characterised by transcriptional dysregulation and resistance to standard therapies, particularly in cases harbouring rearrangements of the KMT2A gene. In this study, investigators examined the transcription factors MEF2C and MEF2D, which were found to be the predominant members of the MEF2 family expressed in this subtype of disease. Both proteins were required to maintain leukemic proliferation and prevent myeloid differentiation.
Rather than acting redundantly, the two transcription factors formed a heterodimer that preserved MEF2C stability through a co stabilisation mechanism. When MEF2D was removed using CRISPR Cas9 mediated gene editing, MEF2C protein levels declined rapidly despite unchanged messenger RNA expression. This indicated that regulation occurred at a post translational level. Further investigation showed that inhibition of the proteasome using MG132 prevented degradation, implicating the ubiquitin proteasome pathway in the control of MEF2C stability.
Degradation Pathway Revealed
To identify the molecular machinery responsible for this degradation, the researchers conducted a CRISPR based screen targeting ubiquitin ligases and deubiquitinases. Analysis highlighted the CUL2 RBX1 complex and its substrate adaptors ZYG11B and ZER1 as critical regulators of MEF2C turnover. These adaptors recognise substrates containing N terminal glycine degrons.
Sequence analysis confirmed that MEF2C contains a conserved N terminal glycine degron essential for its ubiquitylation and degradation. Deletion of ZYG11B or ZER1 stabilised MEF2C protein, prolonged its half-life, and restored proliferative capacity in cells lacking MEF2D. The data indicate that MEF2D acts as a protective partner that shields MEF2C from ubiquitin mediated degradation and thereby maintains MEF2C stability in leukemic cells.
Peptide Strategy Suppresses Leukaemia Progression
To therapeutically disrupt this interaction, the team engineered a competitive peptide derived from the MEF2D N terminus, termed Peptide 54. Expression of this peptide interfered with MEF2C MEF2D binding, triggering degradation of both proteins, induction of myeloid differentiation, and suppression of leukemic proliferation.
In a murine MLL AF9 acute myeloid leukaemia model, inducible expression of Peptide 54 delayed disease progression, reduced leukaemia burden measured by bioluminescence imaging, and extended survival. Genetic deletion of ZYG11B and ZER1 reversed these effects, confirming that the peptide operates through the targeted degradation pathway.
Importantly, Peptide 54 selectively impaired leukemic cells while sparing normal haematopoietic progenitor cells, highlighting a potentially specific therapeutic approach. Collectively, the findings reveal that MEF2C stability depends on a paralog interaction with MEF2D and suggest that disrupting transcription factor co stabilisation may offer a new strategy for treating high risk acute myeloid leukaemia.
Reference
Zhang P et al. Paralog interdependency between MEF2C and MEF2D sustains protein stability and leukemia maintenance in KMT2A-rearranged AML. Abstract 868. ASH Congress, 6-9 December 2025.
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