MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• Developmental toxicity: humans with one working MEF2C copy have severe intellectual disability, absent speech and epilepsy. A drug achieving 50% target occupancy in an infant is pharmacologically imitating that syndrome, in a population this graph already tracks for neurocognitive late effects.
• Not fusion-selective: seven of the ten most MEF2C-depleted leukemia lines are not KMT2A-rearranged, so a MEF2C inhibitor would not be a fusion-directed therapy and would carry no fusion-derived therapeutic index.
• Not orthogonal: MEF2C is downstream of HOXA9, which is downstream of the tether. Combining a menin inhibitor with a MEF2C inhibitor stacks two interventions on the same axis and hedges nothing.
• Undruggable geometry: no experimental structure, a majority-disordered protein, and a DNA-binding MADS dimer as the functional unit.
• A drug that disrupts the MEF2/class IIa HDAC interface induces cross-lineage differentiation toward the monocytic lineage in pre-B-ALL - and myeloid lineage switch is the documented way t(4;11) leukaemia escapes CD19-directed therapy. Using this axis before or alongside blinatumomab or CAR-T could convert a targetable B-lineage disease into an untargetable myeloid one, and the in vitro readout that looks like efficacy is the same readout that would look like resistance.
• The published routes to MEF2C run through LKB1/SIK or through the corepressor-docking groove, so the on-target toxicity is not MEF2C's alone. LKB1/SIK signalling is broadly physiological, and MEF2C haploinsufficiency itself causes severe intellectual disability with epilepsy - so a partial-loss-of-function agent reaching an infant's brain is the risk to size, and neither published strategy reports a central-nervous-system exposure measurement.

1. Is MEF2C required in KMT2A-rearranged lines beyond what its general B-lymphoid requirement explains? Comparing MEF2C dependency in KMT2A-r versus ETV6::RUNX1 and TCF3::PBX1 lines matched for MEF2C expression would answer this and would decide whether MEF2C belongs in this beat at all.
2. Would partial MEF2C inhibition reproduce MEF2C haploinsufficiency syndrome in a developing infant brain? No preclinical model addresses acute partial MEF2C reduction in postnatal neurodevelopment, and until one does, MEF2C should be treated as a paediatric contraindication rather than a target.
3. Does menin inhibition reduce MEF2C, and does residual MEF2C predict escape? MEF2C sits downstream of HOXA9, which sits downstream of the tether, so MEF2C levels under drug are a natural pharmacodynamic readout that nobody has reported.
4. Should the project's triage rule split its constraint axis into developmental haploinsufficiency versus tumour-suppressor constraint? MEF2C and MEN1 have similar LOEUF values and completely different clinical implications for an infant.
5. Do MEF2C puncta in MV4;11 colocalise with nascent transcription at HOXA9 and MEIS1, as MEF2D puncta do at MYC - and does a menin inhibitor dissolve them? The imaging protocol already exists in PMID 35301220 and needs only different FISH probes.
6. Does SIK or LKB1 inhibition diminish histone acetylation at MEF2C-bound enhancers in a KMT2A-rearranged cell? The result exists only in AML with unreported KMT2A status, and MEF2C is a documented member of the KMT2A-fusion output programme co-downregulated with HOXA9. This is the measurement that would move MEF2C from 'undruggable output transcription factor' to 'output transcription factor with a kinase handle' in this disease.
7. Is HDAC7 high or low in t(4;11) infant B-ALL? This project holds it low with a proposal to induce it, and PMID 32913188 reports it overexpressed in BCR-ABL1-negative pre-B-ALL with a strategy to reduce it. The two imply opposite drugs and the discriminating experiment is one immunoblot across t(4;11) and non-KMT2A BCR-ABL1-negative lines.
8. Would CC1007-type disruption of the MEF2/class IIa HDAC interface cause LINEAGE SWITCH rather than differentiation in KMT2A-rearranged B-ALL? Low-dose CC1007 produces cross-lineage differentiation to the monocytic lineage in pre-B-ALL, and this disease's documented escape route from CD19-directed therapy is exactly a myeloid lineage switch. The same drug effect could be therapeutic or could be the resistance mechanism, and nothing distinguishes them in advance.

1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   MEF2C is not DepMap common-essential (mean Chronos -0.036 across 1,258 lines, -0.381 across 57 leukemia lines, 3.4% of lines depleted, leukemia-versus-rest selectivity -0.133); its most depleted leukemia lines span B-ALL, ETV6::RUNX1, TCF3::PBX1, TCF3::HLF, NPM1-mutant AML and KMT2A-rearranged lines; gnomAD reports pLI ~1.0 and LOEUF 0.234 with 6 observed against 50.5 expected loss-of-function variants.

   DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API; gnomAD v4 constraint via the gnomAD GraphQL API; Human Protein Atlas consensus tissue nTPM via the HPA API · Broad Institute DepMap; gnomAD; Human Protein Atlas; Open Targets Platform · Databases 2026
   ▸What this evidence cannot show

   Per-line Chronos values retrieved through Open Targets and means computed by us; DepMap release version unverified. Cell-line lesion assignments in the depletion table were taken from Cellosaurus and from this graph's existing entries, not from DepMap's own annotation. A transcription factor's dependency score is strongly influenced by whether it is expressed at all in a given line.

   ▸Evidence that argues against this (2)

   • MEF2C dysregulation is a driver in leukemias that have nothing to do with KMT2A. In paediatric T-ALL, MEF2C expression defines an immature/early T-cell precursor subgroup, coincides with CDKN1B deletion, and is associated with (or predictive of) the response to glucocorticoid treatment, entirely outside the KMT2A-rearranged setting. A gene that is a driving oncogene in a KMT2A-wild-type disease is not evidence of a KMT2A::AFF1-specific mechanism, and a MEF2C-directed agent would not be a fusion-specific agent. Colomer-Lahiguera S et al. 2017
   • In the largest clinical series, the prognostic signal attributed to MEF2C dissolves on adjustment. Across 751 pretreatment paediatric AML specimens from COG AALL/AAML0531, the top MEF2C quartile had worse CR rate, OS, EFS and relapse risk, but the authors state that these differences were ACCOUNTED FOR by the composition of the cytogenetic/molecular risk groups (16% vs 46% low-risk disease; 68% vs 42% standard-risk), and conclude that MEF2C cooperates with additional pathogenic abnormalities rather than acting as an independent driver. A cooperating marker of adverse-risk composition is a weaker basis for target selection than the entry's co-dependency framing suggests. (Note a published erratum to this paper, PMID 27903291.) Laszlo GS et al. 2015
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   HOXA9 suppression in MLL-rearranged human leukemia cells co-downregulates a programme including HOXA10, MEIS1, PBX3 and MEF2C, and induces proliferation arrest and apoptosis specifically in MLL-rearranged rather than MLL-germline lines (7 versus 10 lines, P = 0.007).

   HOXA9 is required for survival in human MLL-rearranged acute leukemias. · Faber J, Krivtsov AV, Stubbs MC, Wright R, Davis TN, van den Heuvel-Eibrink M, Zwaan CM, Kung AL, Armstrong SA · Blood 2009
   PMID 19056693DOI
   ▸What this evidence cannot show

   RNA interference in cell lines plus primary AML samples; co-downregulation of MEF2C after HOXA9 knockdown establishes that MEF2C is downstream in the same programme but does not establish that MEF2C is independently required. The MEF2C observation is a secondary result of a HOXA9 paper.

   ▸Evidence that argues against this (1)

   • Co-downregulation of a programme on HOXA9 suppression shows the genes move together and does not order them. MEF2C may be downstream of HOXA9, in parallel under a shared upstream driver, or required for HOXA9's own expression. Oncofusion knowledge graph (internal analysis) 2026
3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   Across 54 DepMap leukemia lines MEF2C correlates with MEN1 at r = 0.526 (95% CI 0.301-0.713, permutation p = 0.0002, Holm p = 0.0052), the fifth strongest signal tested and the strongest outside the KMT2A-PSIP1-DOT1L-FLT3 group.

   DepMap co-dependency with MEN1, leukemia-restricted, with bootstrap confidence intervals and permutation testing; analyses/depmap-bootstrap-ci/ in this project · Broad Institute DepMap; Open Targets Platform; analysis run by this project · Database and derived analysis 2026
   ▸What this evidence cannot show

   Our own computation, not peer reviewed, in 54 lines. Because MEF2C's most depleted lines are largely not KMT2A-rearranged, the correlation with MEN1 is more plausibly explained by shared B-lymphoid and myeloid lineage context than by shared mechanism. This is one of the clearest candidates in the panel for a lineage confounder.

   ▸Evidence that argues against this (2)

   • The published work says the actionable variable is MEF2C phosphorylation, not MEF2C dependency. Functional proteomics of patient AML identified MEF2C S222 phosphorylation as the specific marker of primary chemoresistance; a Mef2c knock-in mouse engineered to block that phosphorylation has NORMAL haematopoiesis yet resists MLL-AF9-induced leukemogenesis; and the MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity only in MEF2C-activated cell lines and primary specimens, not in those lacking MEF2C phosphorylation. Two consequences bite on this entry. First, the therapeutic handle is an upstream kinase, not MEF2C, which is what the entry's own note that MEF2C has no experimental structure would predict. Second, the phospho-dead mouse is a direct counter to reading the r = 0.526 co-dependency as a statement about MEF2C protein level: reduced MEF2C dosage is not what is needed and, on the human haploinsufficiency evidence in E4, not what is wanted. Brown FC et al. 2018
   • A caution on the provenance of the number this evidence item reports, stated here so the next reader does not over-read it. The r = 0.526 MEN1 co-dependency is this project's own unreviewed computation on 54 DepMap leukemia lines with an uncontrolled lineage confounder, and two earlier versions of the same analysis reached different conclusions using a criterion since shown to be unstable. MEF2C survives Holm correction in the current 2,743-gene variance-matched null (ana-depmap-null-deep-pool), which is the strongest form the result has taken, but a correlation across cell lines cannot distinguish a shared upstream driver of the immature-leukemia programme from a functional relationship with menin. Where published work speaks, it should outrank this. Broad Institute DepMap; Open Targets Platform; analysis run by this project 2026
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   MEF2C haploinsufficiency, caused by 5q14.3 microdeletion or by point mutation, produces severe intellectual disability with absent speech, hypotonia, stereotypic movements, epilepsy and cerebral malformations; the minimal common deleted region across five unrelated patients encompassed only MEF2C, and a nonsense mutation reproduced the phenotype.

   MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. · Le Meur N, Holder-Espinasse M, Jaillard S, Goldenberg A, Joriot S, Amati-Bonneau P, et al. · Journal of Medical Genetics 2009
   PMID 19592390DOI
   ▸What this evidence cannot show

   Six patients, ascertained through a syndromic-intellectual-disability clinic, so the phenotype is biased toward severe presentations. Constitutional haploinsufficiency from conception is not the same exposure as partial pharmacological inhibition after birth, and the inference that a MEF2C drug would reproduce this syndrome is ours, not the authors'. Nonetheless the direction of risk is unambiguous and the affected organ is the brain of an infant.

   ▸Evidence that argues against this (1)

   • The haploinsufficiency argument constrains one modality but not the one the published work actually proposes. A Mef2c knock-in mouse in which S222 phosphorylation is blocked has NORMAL haematopoiesis while resisting MLL-AF9 leukemogenesis, and the corresponding pharmacology is MARK/SIK kinase inhibition, which leaves MEF2C protein level untouched. So 5q14.3 haploinsufficiency is a decisive objection to degrading MEF2C or halving its dosage, and not an objection to blocking its activating phosphorylation. The entry should not let E4 rule out the MEF2C axis as a whole. Brown FC et al. 2018
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   There is no experimental structure of human MEF2C: a direct RCSB structure search against UniProt accession Q06413 returns zero entries, matching the empty PDB cross-reference list in the UniProt record.

   RCSB PDB structure search against UniProt accession Q06413 (zero results) and UniProtKB Q06413 cross-references, both retrieved via their REST APIs · RCSB Protein Data Bank; UniProt Consortium · Databases 2026
   ▸What this evidence cannot show

   A negative database result is a statement about current deposition and cross-referencing, not about the literature. Structures of the paralogues MEF2A and MEF2B exist and cover a highly conserved MADS/MEF2 domain, so the absence of a MEF2C entry does not mean the fold is unknown. A newly released entry could invalidate this at any time; the query date is 2026-09-18.

   ▸Evidence that argues against this (1)

   • Zero experimental structures for a 473-residue transcription factor is the expected state for a protein that is 60% disordered by UniProt's own annotation, and it is the reason the actionable variable in this graph's phase-2 dossier is the upstream kinase rather than MEF2C itself. RCSB PDB 2026
6. E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProt Q06413 annotates human MEF2C as 473 residues with a MADS-box at 3-57, disordered regions at 91-116, 180-224 and 375-473, a beta domain at 271-278 and a transcription-repressor region at 368-399; Pfam places the SRF-type DNA-binding and dimerisation domain (PF00319) at 10-57.

   UniProtKB Q06413 (MEF2C_HUMAN) and InterPro/Pfam domain assignments, retrieved via the UniProt and InterPro REST APIs · UniProt Consortium; InterPro · Databases 2026
   ▸What this evidence cannot show

   The MEF2 domain proper, conventionally placed immediately C-terminal to the MADS-box, is not separately annotated in this UniProt record, so the boundary between DNA binding and cofactor recruitment is not resolved by these coordinates. Disorder calls are predictions.

   ▸Evidence that argues against this (1)

   • A UniProt domain table is a curated annotation; three disordered regions totalling most of the protein is the substantive content and it is a prediction. UniProt Consortium 2026
7. E_q65_loc1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In MV4;11 cells - a human t(4;11) KMT2A::AFF1 leukaemia line, the index fusion of this graph - MEF2C forms discrete nuclear puncta resolvable by lattice structured-illumination superresolution immunofluorescence; those puncta overlap MEF2D puncta in unperturbed cells, and targeted degradation of MEF2D increases both the number and the intensity of MEF2C nuclear puncta.

   A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia. · Harada T, et al. · Genes Dev 2022;36:368-389 2022
   PMID 35301220DOI
   ▸What this evidence cannot show

   Read from the full text (PMC8973843), Figure 6B/6E/6F/6G and the Methods; the abstract credits superresolution microscopy only to MEF2D and IRF8, so this claim is invisible to any abstract-bounded search. MV4;11 is a MYELOID (AML) line carrying KMT2A::AFF1, so the fusion is the index one and the lineage is not the index infant B-lineage (brief rule 73). The colocalisation with nascent MYC transcription is demonstrated for MEF2D; for MEF2C the published statement is overlap with MEF2D puncta plus increased MEF2C ChIP occupancy after MEF2D degradation. Puncta in fixed cells are not by themselves evidence of phase separation - see this graph's condensate standard, which the paper's own wording ('MEF2C condensates') outruns.

   ▸Evidence that argues against this (1)

   • The same paper establishes that MEF2C is NOT the selective dependency: MEF2C dependency shows no significant selectivity toward KMT2A-rearranged lines and MEF2C is not strongly over-expressed in KMT2Ar leukaemias in BeatAML, while MEF2D is the KMT2A-selective one. So the protein whose subnuclear address is now recorded in the index fusion is the paralog the disease is less specifically addicted to, and an entry that reads 'MEF2C puncta therefore matter in KMT2A-r' overstates it. Harada T et al. 2022
8. E_q65_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Outside leukaemia, MEF2C's nuclear condensation is regulated post-translationally: SENP1 deSUMOylates SUMO2-modified MEF2C at lysine 401, stabilising the protein, and the SENP1 interaction controls MEF2C nuclear condensation in cardiomyocytes.

   Downregulation of SENP1 impairs nuclear condensation of MEF2C and deteriorates ischemic cardiomyopathy. · Xie Y, et al. · Clin Transl Med 2025;15:e70318 2025
   PMID 40341856DOI
   ▸What this evidence cannot show

   Ischaemic cardiomyopathy models in mouse and human cardiomyocytes - as far from infant B-lineage KMT2A::AFF1 as this beat goes. 'Nuclear condensation' here is an imaging descriptor and the paper is not a condensate-mechanism study; by this graph's condensate standard it cannot distinguish phase separation from clustered binding. Abstract only.

   ▸Evidence that argues against this (1)

   • If SUMOylation at K401 governs MEF2C condensation generally, then the puncta measured in MV4;11 are a modification state and not a fixed property, and nothing in the leukaemia work measured MEF2C SUMOylation - so the two results cannot yet be joined. Harada T et al. 2022
9. E_q65_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   MEF2C function in MLL-fusion leukaemia is controlled by a phosphorylation switch rather than by abundance: MEF2C S222 phosphorylation marks primary chemoresistance in patient AML, Mef2c S222A knock-in mice are resistant to MLL-AF9 leukaemogenesis with normal haematopoiesis, and MARK/SIK inhibition confers chemosensitivity only in MEF2C-phosphorylated cells.

   MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. · Brown FC, et al. · Cancer Discov 2018;8:478-497 2018
   PMID 29431698DOI
   ▸What this evidence cannot show

   Murine MLL-AF9 myeloid leukaemia plus human AML lines and primary specimens - not KMT2A::AFF1 and not infant B-lineage (brief rule 73). This is a modification-state result, not a localisation one; it is recorded here because a modification switch is the most likely determinant of the puncta measured above and nobody has tested that. Abstract only. NOTE, and it is a title-drift hazard worth recording: the PubMed title for this record contains an INVISIBLE NON-BREAKING SPACE (U+00A0) between 'for' and 'Chemotherapy'. The title stored here was copied verbatim from the fetched efetch record and preserves it, so a character-by-character diff returns zero. A hand-typed or hand-corrected title would silently substitute an ordinary space and no reader could see the difference. Two of the 47 PMIDs this beat introduced carry U+00A0 in the title - the other is PMID 22544066, between 'fusion' and 'to'.

   ▸Evidence that argues against this (1)

   • A phosphorylation requirement demonstrated in MLL-AF9 myeloid disease is not transferable to KMT2A::AFF1 infant B-ALL, where MEF2C's partner circuitry differs; the core-regulatory-module paper finds MEF2C dependency non-selective across KMT2A-rearranged lines at all. Harada T et al. 2022
10. E_q69_ct1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In MICE, Mef2c deficiency produces profound defects in the production of B cells, T cells, natural killer cells and common lymphoid progenitors together with an enhanced myeloid output; in multipotent progenitors Mef2c is required for proper expression of several key lymphoid regulators and for restriction of the myeloid fate, and Mef2c is a critical transcriptional target of PU.1 during lymphopoiesis.

    Regulation of lymphoid versus myeloid fate 'choice' by the transcription factor Mef2c. · Stehling-Sun S, Dade J, Nutt SL, DeKoter RP, Camargo FD · Nat Immunol 2009
    PMID 19169261DOI
    ▸What this evidence cannot show

    Abstract read in full; full text not read. Murine normal haematopoiesis, not leukaemia and not human (brief rule 73). 'Fate choice' here is a population-level output measurement, not a single-cell lineage-tracing result.

    ▸Evidence that argues against this (1)

    • The same year's Blood paper from a different group shows Mef2c is required for MONOCYTIC differentiation and restrains granulopoiesis in murine bone marrow, so Mef2c is not simply a lymphoid-restricting factor; its loss shifts myeloid output in a direction the lymphoid paper does not resolve. Schüler A et al. 2008
11. E_q69_ct2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In murine bone marrow, constitutive Mef2c expression increases monopoiesis at the expense of granulopoiesis while Mef2c(Delta/-) marrow shows reduced monocytic differentiation in response to cytokines; the effect correlates with c-Jun transcript levels and not with PU.1, C/EBPalpha or JunB.

    The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate. · Schüler A, Schwieger M, Engelmann A, Weber K, Horn S, Müller U, Arnold MA, Olson EN, Stocking C · Blood 2008
    PMID 18326819DOI
    ▸What this evidence cannot show

    Abstract read in full; full text not read. Murine, normal haematopoiesis, retroviral overexpression for the gain-of-function arm - an overexpression fate shift is weak evidence about the endogenous protein's dose. No leukaemia measurement in this arm.

    ▸Evidence that argues against this (1)

    • The lymphoid-fate paper reports that Mef2c-deficient mice have ENHANCED myeloid output, which is not obviously reconcilable with Mef2c being required for monocytic differentiation. The two results were obtained in different Mef2c alleles and different readouts and the field has not resolved them; this entry records the tension rather than choosing. Stehling-Sun S et al. 2009
12. E_q69_cs1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    MEF2C S222 phosphorylation is a specific marker of primary chemoresistance in patient AML; Mef2cS222A/S222A knock-in mice show normal haematopoiesis but are resistant to MLL-AF9-induced leukaemogenesis, MEF2C phosphorylation is required for leukaemia stem cell maintenance and is induced by MARK kinases, and the MARK/SIK inhibitor MRT199665 causes apoptosis and confers chemosensitivity in MEF2C-activated human AML lines and primary patient specimens but not in those lacking MEF2C phosphorylation.

    MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. · Brown FC, Still E, Koche RP, Yim CY, Takao S, Cifani P, Reed C, Gunasekera S, Ficarro SB, Romanienko P, Mark W, McCarthy C, de Stanchina E, Gonen M, Seshan V, Bhola P, O'Donnell C, Spitzer B, Stutzke C, Lavallée VP, Hébert J, Krivtsov AV, Melnick A, Paietta EM, Tallman MS, Letai A, Sauvageau G, Pouliot G, Levine R, Marto JA, Armstrong SA, Kentsis A · Cancer Discov 2018
    PMID 29431698DOI
    ▸What this evidence cannot show

    Abstract read in full; full text not read. Adult AML - human primary specimens and cell lines - plus murine MLL-AF9; NOT infant B-lineage KMT2A::AFF1 (brief rule 73). This PMID is already cited elsewhere in this entry; it is re-fetched here and cited for the cell-state claim, which is a different claim. MRT199665 is a MARK/SIK inhibitor, so the pharmacology is upstream of MEF2C and not a MEF2C-directed agent.

    ▸Evidence that argues against this (1)

    • The knock-in mice have NORMAL haematopoiesis, which is the paper's own strongest internal limit on the cell-state claim: whatever MEF2C phosphorylation does for a leukaemia stem cell, it is dispensable for the normal stem and progenitor compartments the leukaemia arises from. A therapeutic reading that treats MEF2C phospho-state as a general stem-cell dependency is contradicted by the authors' own genotype. Brown FC et al. 2018
13. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    MEF2C's OUTPUT IS READ OUT AS HISTONE ACETYLATION AT ITS OWN ENHANCERS, AND THE HANDLE IS AN UPSTREAM KINASE: a domain-focused CRISPR screen revealed an essential role for LKB1 and its salt-inducible kinase effectors (SIK3, partially redundant with SIK2) in maintaining MEF2C function in acute myeloid leukaemia; a key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C; targeting LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukaemia cells of the output of this essential transcription factor; and MEF2C-dependent leukaemias are sensitive to on-target chemical inhibition of SIK activity.

    LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. · Tarumoto Y, Lu B, Somerville TDD, et al. · Mol Cell 2018
    PMID 29526696DOI
    ▸What this evidence cannot show

    Abstract read from the eutils record; full text not read in this tranche. ACUTE MYELOID LEUKAEMIA - not B-lineage, not infant, and the abstract does not state KMT2A status, so this is not index-fusion evidence and rule 73 applies to any downstream claim. 'Histone acetylation' is not resolved to a residue in the abstract, so no specific acetyl mark (H3K27ac, H3K9ac, H4K16ac) can be asserted; the graph must not fill that in. HDAC4 is named as the key substrate 'in this context', and class IIa HDACs are a partially redundant family (HDAC4/5/7/9) all of which bind MEF2, so attributing the effect to HDAC4 alone is the paper's emphasis rather than a demonstrated exclusivity. SIK3 is partially redundant with SIK2 by the authors' own statement, which bounds how clean a single-kinase target this is. Not cited anywhere in this corpus before 2026-09-21, verified with scripts/check-citation-reuse.py.

    ▸Evidence that argues against this (1)

    • A route to blocking MEF2C function does not make MEF2C a safe target, and this entry's strongest fact argues the opposite. MEF2C haploinsufficiency - by 5q14.3 microdeletion or point mutation - produces severe intellectual disability with absent speech, stereotypies and epilepsy in humans. A chemical strategy that succeeds in depriving leukaemia cells of MEF2C output is, by construction, a strategy for producing partial MEF2C loss of function, in an infant, during the period of most rapid neurodevelopment. The SIK route may be more tolerable than direct MEF2C inhibition or may be less so, since LKB1/SIK signalling has its own broad physiology; nothing read here addresses it. Le Meur N et al. 2010
14. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    THE SAME ERASER-DOCKING AXIS IS DRUGGED FROM THE OTHER SIDE IN B-LINEAGE LEUKAEMIA: CC1007, a BML-210 analogue, is designed to inhibit class IIa HDACs indirectly by binding myocyte enhancer factor-2 (MEF2) and blocking the recruitment of class IIa HDACs to MEF2-targeted genes; in BCR-ABL1-negative pre-B-ALL cell lines and primary patient-derived cells it showed antileukaemic activity in vitro and in vivo and prolonged median survival of pre-B-ALL-bearing mice, HDAC7 was overexpressed in those cells relative to normal bone marrow, and CC1007 reduced HDAC7 binding at the promoters of monocyte-macrophage-specific genes via inhibition of HDAC7 expression and of the HDAC7:MEF2C interaction, with low-dose treatment producing cross-lineage differentiation toward the monocytic lineage without significant apoptosis.

    A small molecular compound CC1007 induces cross-lineage differentiation by inhibiting HDAC7 expression and HDAC7/MEF2C interaction in BCR-ABL1- pre-B-ALL. · Wang Z, Zhang Y, Zhu S, et al. · Cell Death Dis 2020
    PMID 32913188DOI
    ▸What this evidence cannot show

    Abstract read from the eutils record; full text not read in this tranche. The cohort is BCR-ABL1-NEGATIVE pre-B-ALL, which is defined by what it is not: the abstract does not report KMT2A rearrangement status for any line or patient, so whether any t(4;11) case is included is unknown and this cannot be read as index-fusion evidence. The readout is HDAC7 OCCUPANCY at specific promoters by ChIP plus expression, NOT a histone acetylation measurement, so no mark is quantified. CC1007's mechanism is 'designed to' bind MEF2 and block class IIa HDAC recruitment - a design intent plus a downstream consequence, with no direct binding measurement reported in the abstract; BML-210 analogues have documented polypharmacology. Class IIa HDACs are catalytically near-dead against acetyl-lysine in vitro, so 'inhibiting class IIa HDACs' here means disrupting a corepressor scaffold rather than blocking a deacetylase reaction. Not cited anywhere in this corpus before 2026-09-21.

    ▸Evidence that argues against this (1)

    • The direction of the HDAC7 intervention is contested in leukaemia generally, and this graph already holds the opposite proposal for the index disease. HDAC7 has been characterised as a transcriptional repressor that PROMOTES apoptosis and downregulates c-Myc in particular types of leukaemia and lymphoma - i.e. as a tumour-suppressive activity one would want to increase - and this project's own identifier notes record HDAC7 as reported LOW in t(4;11) infant B-ALL with the proposal being to INDUCE it, against HDAC9 high with the proposal to repress it. So a strategy that lowers HDAC7 expression and function may be exactly wrong for the index population, and the two claims rest on different cohorts with no shared samples. This is recorded as an unresolved direction conflict, not a refutation. Barneda-Zahonero B et al. 2015

• ← co-occurs withHDAC9 - the only HDAC with a KMT2A-rearrangement expression signature across 211 paediatric patients, and it is high, prognostic, and independent of partner and lineage

  the KMT2A-rearranged signature is high HDAC9 with high MEF2D, its recruiting MEF2-family factor

• related to →MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed

  Counter-evidence axis: MEF2C survives the deep-pool null and MEIS1 does not (Holm 0.067); both are outputs of the same HOXA9 programme rather than independent nodes

• supports →Six times the null pool, and the criterion I had been using turns out to be the problem (run)

  MEF2C is one of six genes surviving Holm correction against the 2,743-gene variance-matched null (r 0.526)

• regulates →HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it

  MEF2C is co-downregulated with the HOXA9 output programme in MLL-rearranged cells

• co-occurs with →MEN1 / menin — the adaptor the fusion cannot work without

  leukemia co-dependency r=0.53; plausibly a lineage effect

• part of →Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133

  output-program transcription factor, not a fusion-complex subunit

• related to →What the treated brain looks like later: neurocognitive late effects after CNS-directed therapy in infancy

  MEF2C haploinsufficiency causes severe intellectual disability and epilepsy in humans

• ← regulatesHOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it

  MEF2C is part of the HOXA9-dependent output programme

• ← regulatesThe experiment that refutes cycle 55's headline was already public: VTP-50469 collapses MEIS1 32-fold in the same line where MI-2-2 left it untouched - and HOXA9 was never actually measured by either dataset

  MEF2C -3.29 at day 2 and -4.35 at day 7 under VTP-50469 in RS4;11

• ← related toWhere else in a child is the target switched on? (run)

  11.6x higher in cerebral cortex than marrow, and MEF2C haploinsufficiency causes the 5q14.3 neurodevelopmental syndrome

• ← supportsGiving the reopening conditions an owner, and the first run changes two decisions (run)

  the redefinition to the upstream kinase is confirmed by oral SIK2/3 inhibitors with in vivo efficacy in MV4-11

• regulates →SOCS2 (O14508) - a MENIN-INHIBITOR-SELECTIVE member of the signature, a cullin-5 E3 substrate receptor, and its likeliest upstream regulator is MEF2C rather than ATF4

  lentiviral Mef2c transduction upregulates Socs2 in murine haematopoietic precursors while Ikzf1 does not (PMID 25858143); MEF2C falls 4.35 log2 under VTP-50469 and only 1.71 under EPZ5676, which explains SOCS2's menin-selectivity without the ISR

• ← supportsATF4's own transcript does NOT move under either menin inhibitor - and the whole ISR arm is reproduced by a DOT1L inhibitor, so it is not a menin-interface readout

  MEF2C discriminates the two compounds by 2.65 log2 (-4.35 vs -1.71), which is why it and MEIS1 are the defensible pharmacodynamic markers for menin engagement and the ISR genes are not

• ← related toMEF2C loses occupancy under VTP-50469 in all three human MLL-rearranged lines (MLL1-N 0.18 / 0.25 / 0.04 over floor), which resolves Q117's one locus-level disagreement with the published account in the paper's favour and localises the disagreement to the murine system

  MEF2C MLL1-N share ratio 0.181 / 0.248 / 0.040 over floor in RS4;11 / MOLM13 / ML-2, summed over the three MEF2C TSS windows

• ← related toUnder EPZ5676 the canonical KMT2A-fusion targets look like they lose H3K79me2 far more than the genome (p=0.017 and p=0.0004), and against a baseline-matched null the entire effect vanishes (p=0.34 and p=0.22) - eight of the ten are simply top-decile genes

  baseline decile 5 in RS4;11, retains 7.03% - the most spared of the ten, and that tracks its low baseline

• part of →Transcription factories and Pol II clusters - no KMT2A::AFF1 imaging, condensate evidence for SEC and MLL-ENL, and 3D-FISH that actively contradicts the factory story for t(4;11)

  MEF2C forms nuclear puncta overlapping MEF2D puncta in MV4;11 (KMT2A::AFF1), and the MEF2D puncta colocalise with sites of nascent MYC transcription - measured by lattice SIM

• related to →The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove

  the source paper calls the MEF2C puncta 'condensates'; by this graph's standard fixed-cell puncta cannot separate phase separation from clustered binding, and the entry records puncta rather than condensates

• ← related toHDAC7 - the eraser the index fusion silences, where the proposed therapy is to INDUCE the HDAC, and two 2024-2025 papers point in opposite directions

  HDAC7 is the corepressor whose PML-body sequestration releases MEF2 target promoters; both entries are in this tranche and neither has been co-imaged in a KMT2A-rearranged cell

• expressed in →Lymphoid-primed multipotent progenitor (LMPP) — the bi-potent cell that explains how one fusion makes two lineages

  Mef2c acts in multipotent/lymphoid-primed progenitors, where it is required for lymphoid regulator expression and restriction of the myeloid fate (murine; PMID 19169261)

• expressed in →Multipotent progenitor (MPP) — the stage where the undifferentiated KMT2A-r infant leukaemias map

  in multipotent progenitors Mef2c is required for proper expression of key lymphoid regulators, downstream of PU.1 (murine; PMID 19169261)

• regulates →Common lymphoid progenitor (CLP) — the CD10-positive lymphoid route that infant KMT2A leukaemia appears NOT to take

  Mef2c deficiency causes profound loss of common lymphoid progenitors alongside B, T and NK cells (murine; PMID 19169261)

• regulates →Monocyte — the graph's most-discussed undefined cell identity, and the confound sitting under its own DepMap haem signal

  Mef2c increases monopoiesis at the expense of granulopoiesis and Mef2c(Delta/-) marrow shows reduced monocytic differentiation (murine; PMID 18326819)

• regulates →The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell

  MEF2C S222 phosphorylation is required for leukaemia stem cell maintenance; the S222A knock-in mouse has normal haematopoiesis yet resists MLL-AF9 leukaemogenesis (PMID 29431698)

• related to →The relapse-initiating persister state — present at diagnosis, identifiable before a single dose is given, and defined by basal glucocorticoid-response activation plus small size plus quiescence

  MEF2C S222 phosphorylation is a marker of PRIMARY chemoresistance in patient AML and MARK/SIK inhibition restores chemosensitivity only in phospho-positive specimens (PMID 29431698)

• binds →HDAC7 - the eraser the index fusion silences, where the proposed therapy is to INDUCE the HDAC, and two 2024-2025 papers point in opposite directions

  HDAC7 is recruited to MEF2 binding sites at myeloid-gene promoters through a specific interaction with MEF2C in pre-B cells; the two genes in this tranche share one repressive module (PMIDs 23696748, 27810920)

• ← regulatesOnly a handful of loci lose fusion occupancy under a menin inhibitor, and they are the same few whether menin is drugged or deleted: MEIS1, MEF2C, JMJD1C - not HOXA, not MYB

  one of three loci at which the fusion genuinely loses occupancy under the drug

• related to →H3K27ac - named in 40 entries with no entry of its own, and the strongest KMT2A::AFF1 measurement of it is invisible to every abstract search

  MEF2C's OUTPUT IS READ AS HISTONE ACETYLATION AT ITS OWN ENHANCERS: targeting LKB1 or SIK3 - whose substrate HDAC4 is a repressive MEF2C cofactor - diminishes histone acetylation at MEF2C-bound enhancers in AML. RESIDUE NOT SPECIFIED in the source, so this edge points at the acetylation family's representative node and must not be read as an H3K27ac-specific measurement.

• related to →Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here

  RECRUITER OF AN ERASER, NOT A WRITER: MEF2C is a MADS-box transcription factor with no chromatin domain whose epigenetic identity is as the docking platform for class IIa histone deacetylases (HDAC4/5/7/9), which are its repressive cofactors. Both published routes to drugging MEF2C act on that axis rather than on MEF2C itself.

• binds →HDAC7 - the eraser the index fusion silences, where the proposed therapy is to INDUCE the HDAC, and two 2024-2025 papers point in opposite directions

  HDAC7:MEF2C interaction, and a DIRECTION CONFLICT: CC1007 reduces HDAC7 expression and the HDAC7:MEF2C interaction in BCR-ABL1-negative pre-B-ALL, where HDAC7 is reported OVEREXPRESSED - while this project records HDAC7 as LOW in t(4;11) infant B-ALL with a proposal to INDUCE it. Overlapping populations, opposite directions, unresolved.

• ← testsAuditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails

  redefinition confirmed: the handle is S222 phosphorylation and the upstream MARK/SIK kinases