BENC - the MYC blood enhancer cluster 1.7 Mb downstream, required for MLL-AF9 leukaemia maintenance, and named in zero entries of this graph until now
also called BENC · blood enhancer cluster · BDME · BRD4-dependent MYC enhancer · the +1.7 Mb Myc enhancer cluster · Myc super-enhancer +1.7 Mb
A stretch of DNA nearly two million letters away from the MYC gene acts as its volume dial in blood cells, and deleting it wipes out MYC in blood stem cells entirely. The same stretch is required to keep MLL-AF9 leukaemia alive in mice - and this knowledge graph, which argues about MYC in dozens of entries, had never once named it.
The same thing, for a scientist
BENC is an evolutionarily conserved cluster of enhancer modules located **1.7 Mb downstream of the MYC transcription start site**, previously labelled a super-enhancer. Deletion in mice causes complete loss of Myc expression in haematopoietic stem cells and progenitors, phenocopying conditional Myc deletion: accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells. The cluster comprises multiple modules with selective activity recruiting GFI1B, RUNX1 and MYB, and specific Myc levels across the haematopoietic hierarchy are set by the combinatorial and additive activity of the individual modules. **BENC is essential for the maintenance of MLL-AF9-driven leukaemia in mice**, and one BENC module shows increased chromatin accessibility in human AML stem cells relative to blasts, correlating with MYC expression and with patient outcome [E1]. The same element, under the name **BDME**, is the one at which the inv(16) fusion inhibitor AI-10-49 drives a BRG1-to-RING1B exchange [E2]; under no name at all, it is the 'cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc' at which SWI/SNF was first shown to act in MLL-AF9 leukaemia [E3]. Copy-number amplification of BENC occurs recurrently in B-precursor ALL cell lines, where it drives MYC expression [E4], and Shi et al. note the region is focally amplified in about 3% of AMLs [E3]. **Nobody has measured BENC in KMT2A-rearranged infant B-ALL, and nobody has measured what a menin inhibitor does to it.**
The absence this entry closes, and how it was measured
On 2026-09-20 a word-boundary regex \bBENC\b over all 1,510 node JSON files in this graph returned zero entries; so did the phrase blood enhancer cluster. This beat's dispatch brief records that a naive substring search had suggested 79 entries - a substring artefact, because benc occurs inside ordinary words. The correction was made by the coordinator before dispatch and is confirmed here independently.
The cost of that absence is specific and large. mechanism-baf-myc-contradiction-two-papers-one-model is a live, recorded contradiction about whether MYC is the node downstream of SWI/SNF in MLL-AF9. The element at the centre of the paper on one side of that contradiction is BENC, and the graph could not say so because it had no word for it.
One element, three names, and none of them is searchable
This is the sharpest identifier trap this beat found, and it is a noncoding element, a class for which none of the brief's existing rules (62-69, all about gene symbols) applies. PubMed counts run 2026-09-20:
| query | records | what they are |
|---|---|---|
"blood enhancer cluster"[tiab] | 3 | Bahr 2018, Watanabe 2024, one MECOM/iPSC paper |
BENC[tiab] AND (MLL OR KMT2A) | 1 | Bahr 2018 only |
BDME[tiab] | 14 | none of them this element - Boswellia dalzielii methanol extract, bipolar disorder manic episode, breast duct microendoscopy, bis-demethoxycurcumin |
"BRD4-dependent MYC enhancer"[tiab] OR "BRD4-mediated MYC enhancer"[tiab] | 0 | the phrase appears only in body text |
So: the canonical acronym retrieves three papers; the alternative acronym retrieves fourteen papers of pure noise and zero signal; and the spelled-out name retrieves nothing. Shi et al. 3 - the paper that found the element - give it no name at all, describing it as 'a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc'. The only reliable retrieval key is the coordinate description, 1.7 Mb downstream, which is not an indexable token.
This is written up separately as concept-a-noncoding-element-has-no-symbol-and-three-names, because it generalises past MYC and because a counted absence on any enhancer in this graph is currently unbounded by construction.
What is established in this disease, and what is not
Established. BENC deletion abolishes Myc in HSC/progenitors and is required for MLL-AF9 leukaemia maintenance in mice 1. SWI/SNF (Brg1) and BRD4 occupy the cluster and Brg1 is required there to maintain transcription-factor occupancy and long-range looping to the Myc promoter in MLL-AF9 leukaemia 3. Deletion of the RUNX1 site within the E3 module alone reduces MYC by 40-50% and viability by 60-70% in an inv(16) human line 2 - a module-level, not cluster-level, functional test.
Not established, and these are the gaps worth the lab's attention.
- No menin-inhibitor measurement at BENC exists. A PubMed query joining menin-inhibitor terms with MYC returns 13 records (2026-09-20) and none of them reports enhancer-level occupancy at this cluster.
hyp-menin-inhibition-swaps-brg1-for-ring1b-at-bencstates the resulting prediction. - No BENC measurement in KMT2A::AFF1 infant B-ALL. The murine work is MLL-AF9 myeloid; the B-lineage evidence is copy-number amplification in BCP-ALL cell lines 4, which is an in-vitro immortalisation phenotype by the authors' own framing and says nothing about the infant disease.
- Module-level resolution is missing in every leukaemia context except inv(16). Bahr et al. show the modules are individually deletable with graded effects across the hierarchy 1; the leukaemia experiments in this graph's evidence base treat the cluster as one object.
| element class | enhancer cluster / super-enhancer, modular |
|---|---|
| target gene | gene-myc |
| position | +1.7 Mb downstream of the MYC transcription start site |
| coordinates hg38 | not asserted - no paper read in full by this beat states the interval in hg38, and this graph's standing rule is not to read a coordinate off a figure |
| modules | multiple, individually deletable with graded effects across the haematopoietic hierarchy (PMID 29342133); Pulikkan numbers five conserved elements E1-E5 within it (PMID 29958106) - the two numbering schemes are NOT aligned here |
| polycomb factor recruited on drug | RING1B, at ME1, ME2 and BDME-E3, in inv(16) under AI-10-49 (PMID 29958106) |
| germline deletion phenotype mouse | complete loss of Myc in HSC/progenitors; accumulation of differentiation-arrested multipotent progenitors; loss of myeloid and B cells |
| required for mll af9 leukaemia maintenance | true |
| focal amplification frequency aml PCT | 3 |
| copy number amplification in bcp all | recurrent in cell lines (PMID 38923173); no primary-sample survey found |
| measured under a menin inhibitor | false |
| measured in kmt2a aff1 infant b all | false |
| named in graph entries when written | 0 |
| count method | word-boundary regex /\bBENC\b/ and the phrase 'blood enhancer cluster' over all 1,510 node JSON files, run 2026-09-20 |
names in the literature — the numbers behind the chart
[
{
"name": "BENC (blood enhancer cluster)",
"coined_by": "PMID 29342133",
"pubmed_tiab_records_2026_09_20": 3
},
{
"name": "BDME (BRD4-dependent / BRD4-mediated MYC enhancer)",
"used_by": "PMID 29958106",
"pubmed_tiab_records_2026_09_20": 14,
"note": "all 14 are unrelated - Boswellia dalzielii methanol extract, bipolar disorder manic episode, breast duct microendoscopy, bis-demethoxycurcumin. Zero signal."
},
{
"name": "unnamed - 'a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc'",
"used_by": "PMID 24285714",
"pubmed_tiab_records_2026_09_20": 0,
"note": "retrievable only by coordinate description, which is not an indexable token"
}
]transcription factors recruited
[ "GFI1B", "RUNX1", "MYB" ]
chromatin factors occupying
[ "SWI/SNF (BRG1/SMARCA4)", "BRD4" ]
- MYC enhancer usage in this exact model is documented to be plastic: BET-inhibitor resistance proceeds by activating a different focal MYC enhancer that recruits WNT machinery. Any intervention aimed at BENC has a published escape route in the literature before it is attempted.
- BENC is required for normal HSC Myc expression, and its deletion in mice destroys myeloid and B-cell output. A therapeutic strategy that shuts BENC down is shutting down normal haematopoiesis unless it is module-selective, and module selectivity has not been demonstrated in a leukaemia context.
- The element is focally amplified in a minority of AMLs and recurrently amplified in BCP-ALL cell lines. Amplification is a plausible route to enhancer-directed drug resistance by raising the number of copies that would have to be silenced.
- Because the element has three names and none of them retrieves the literature reliably, a future counted absence about BENC - or about any enhancer - will be unbounded by construction unless the searcher already knows all three names.
- What does a menin inhibitor do at BENC in a KMT2A-rearranged cell? No published measurement exists; this is the single most actionable gap this beat found.
- Is BENC required in KMT2A::AFF1 B-lineage leukaemia as it is in MLL-AF9 myeloid leukaemia? The B-lineage evidence is confined to cell-line copy-number amplification.
- Which BENC modules matter in leukaemia as opposed to in normal haematopoiesis? Bahr et al. show module-level resolution is achievable; a module whose deletion spares normal HSC Myc and kills the leukaemia would be a genuine therapeutic object.
- Is the WNT-recruiting focal MYC enhancer of the BET-inhibitor-resistant state inside BENC or a separate element? The answer determines whether BENC is escapable under drug pressure.
- Has anyone surveyed BENC copy number in primary infant KMT2A-rearranged ALL? The cell-line finding raises the question and no primary series was located.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
An evolutionarily conserved region 1.7 Mb downstream of Myc, comprising multiple enhancer modules that recruit GFI1B, RUNX1 and MYB and collectively function as a blood enhancer cluster (BENC), is essential for Myc expression in haematopoietic stem cells and progenitors, is essential for maintenance of MLL-AF9-driven leukaemia in mice, and contains a module whose chromatin accessibility is higher in human AML stem cells than in blasts in a way that correlates with MYC expression and patient outcome.
A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies. · Bahr C, von Paleske L, Uslu VV, Remeseiro S, Takayama N, Ng SW, et al. · Nature 2018What this evidence cannot show
The genetics are mouse; the human evidence is chromatin accessibility in AML stem cells versus blasts, which is an association with MYC expression and outcome, not a perturbation. MLL-AF9 is the only fusion tested. The paper was not readable in full by this beat - Europe PMC returns no PMCID for it - so module identities, coordinates and the exact leukaemia assay are known only at abstract level and are not asserted here.
Evidence that argues against this (1)
- Cruickshank et al. report that in human MLL-rearranged cells, SWI/SNF subunits are NOT required for expression of c-MYC-regulated genes, explicitly contrasting with the mouse results. That does not contradict BENC's requirement (a different perturbation on a different object) but it does show that mouse MLL-AF9 MYC-enhancer results have failed to transfer to human cells once already, which is the relevant risk for this claim. Cruickshank VA et al. 2015
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In inv(16) AML cells, the primary drug-induced RUNX1 peak lies within the BDME super-enhancer 1.7 Mb downstream of the MYC TSS, at element E3 of its five conserved elements; RING1B is recruited specifically to the ME1, ME2 and E3 enhancers but not to the non-myeloid N-ME control, BRG1 is lost there, and CRISPR deletion of the RUNX1 site within each of ME1, ME2 or E3 individually reduces MYC expression by 40-50% and viability by 60-70%.
CBFbeta-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia · Pulikkan JA, Hegde M, Ahmad HM, Belaghzal H, Illendula A, Yu J, O'Hagan K, Ou J, Muller-Tidow C, Wolfe SA, Zhu LJ, Dekker J, Bushweller JH, Castilla LH · Cell 2018What this evidence cannot show
inv(16) AML, not KMT2A-rearranged, and largely one human cell line (ME-1). The element identity claim - that Pulikkan's BDME is Bahr's BENC - rests on both papers placing their element 1.7 Mb downstream of the MYC TSS and on Pulikkan explicitly citing Shi et al. 2013 for it; no paper states the equivalence in those words, and this entry asserts it as a reading of the two texts, made from the full text of Pulikkan (PMC6211564, read 2026-09-20) and the abstract of Bahr. Module numbering differs between papers (E1-E5 in Pulikkan) and is not aligned here.
Evidence that argues against this (1)
- Pulikkan et al. assay H3K27me3, a PRC2 mark, as their repressive readout, not H2AK119ub, the direct catalytic product of RING1B. So the paper establishes that RING1B arrives and that H3K27me3 rises; it does not establish which PRC1 flavour acted, and in particular does not establish PRC1.1. Sijm et al. show H2AK119ub1 dosage is largely uncoupled from H3K27me3, which means the H3K27me3 gain cannot be used to infer the size of the PRC1 catalytic event. Sijm A et al. 2022
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Leukaemia cells require SWI/SNF for survival and self-renewal, with Myc as a key target; a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc is occupied by SWI/SNF and BRD4, Brg1 is required there to maintain transcription-factor occupancy and long-range looping to the Myc promoter, and the region coincides with a locus focally amplified in about 3% of acute myeloid leukaemias.
Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. · Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, et al. · Genes Dev 2013What this evidence cannot show
Mouse MLL-AF9 (the RN2 model carries a cooperating NrasG12D allele), and the paper names no element - it describes it by coordinate, which is why it is unreachable by any acronym search. Its MYC conclusion is directly contested by PMID 26571505 in human cells; see mechanism-baf-myc-contradiction-two-papers-one-model. The 3% focal-amplification figure is an association across AML cohorts, not a functional claim.
Evidence that argues against this (1)
- Cruickshank et al., studying the same three SWI/SNF subunits in human MLL-rearranged cells, found they are required for haematopoietic-stem-cell-associated gene expression but, in explicit contrast to the mouse results, NOT for expression of c-MYC-regulated genes. The MYC arm of Shi et al. therefore has a published human-cell failure to replicate. Cruickshank VA et al. 2015
- E4weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
Recurrent copy-number alterations of the blood enhancer cluster (BENC-CNA) occur in B-precursor acute lymphoblastic leukaemia cell lines, where BENC acts as a super-enhancer driving MYC expression and possibly contributing to immortalisation and proliferative advantage in vitro.
Acquired copy number amplification at the MYC enhancer in human B-precursor acute lymphoblastic leukemia cell lines. · Watanabe A, Wang L, Tan TK, Urayama KY, Kizuki T, Komatsu C, et al. · Cancer Sci 2024What this evidence cannot show
Cell lines only, and the title word is 'Acquired' - the authors' own framing is that these are alterations acquired during immortalisation in vitro, not lesions of the patient disease. The abstract is a short structured summary with no KMT2A-rearranged subgroup identified. Graded weak and cited to establish that the element is under selection in B-lineage contexts at all, which is the only B-lineage BENC evidence this beat found.
Evidence that argues against this (1)
- The same element's amplification in primary disease is reported at only ~3% in AML by Shi et al., so a high frequency in cell lines against a low frequency in primary material is itself evidence that the cell-line finding is a culture-adaptation phenomenon rather than a disease lesion. No primary-sample BENC copy-number survey in infant KMT2A-rearranged ALL was found. Shi J et al. 2013
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
BET-inhibitor-resistant leukaemias are characterised by remodelled regulatory landscapes involving activation of a focal MYC enhancer that recruits WNT machinery, restoring MYC transcription; the screen was performed in an MLL-AF9;NrasG12D AML mouse model and PRC2 suppression promoted BET-inhibitor resistance.
Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. · Rathert P, Roth M, Neumann T, Muerdter F, Roe JS, Muhar M, et al. · Nature 2015What this evidence cannot show
The 'focal MYC enhancer' activated in resistance is described as focal and WNT-recruiting; the abstract does not state whether it lies within BENC, so this entry does NOT assert that it does. Cited for a different point: that in the same MLL-AF9;NrasG12D model used by Shi et al., MYC enhancer usage is plastic and re-routes under chromatin-drug pressure. That plasticity is a mechanism by which a BENC-directed intervention could be escaped.
Evidence that argues against this (1)
- Bahr et al. report that BENC deletion abolishes Myc in HSC/progenitors completely and is required for MLL-AF9 leukaemia maintenance, which argues that at least in the untreated state there is no redundant enhancer able to substitute. Whether the WNT-recruiting focal enhancer of the resistant state is inside BENC or is a genuine alternative element is the unresolved point between these two papers. Bahr C et al. 2018
sets MYC level in blood cells from +1.7 Mb; deletion abolishes Myc in mouse HSC/progenitors
BENC is required for maintenance of MLL-AF9-driven leukaemia in mice
Brg1 occupies the cluster and is required there for TF occupancy and looping to the Myc promoter
BRD4 occupies the cluster; the alternative name BDME is built on this
RUNX1 is one of the TFs recruited by BENC modules, and the drug-induced RUNX1 peak in inv(16) is at element E3
RING1B is recruited to ME1, ME2 and BDME-E3 under CBFbeta-SMMHC inhibition, replacing BRG1
- related to →Is MYC the node? Two papers, the same MLL-AF9 model, opposite answers - and the second one failed to rescue
this is the element at the centre of the Shi/Cruickshank disagreement, which the graph previously had no name for
a named, functionally validated distal enhancer module for a KMT2A-relevant oncogene
BENC contacts the MYC promoter across 1.7 Mb; the inv(16) study confirms the physical connection by enhancer-interaction analysis
- related to →KMT2A-rearranged acute lymphoblastic leukaemia
recurrent BENC copy-number amplification in BCP-ALL cell lines drives MYC; no KMT2A-rearranged or primary-sample survey exists
the element at which the swap occurs (BDME element E3, plus ME1 and ME2)
the worked example: BENC, BDME, and no name at all
the element the hypothesis addresses
the element at the centre of the dispute, named for the first time in this graph
is the cluster even active in the index disease? every published result is myeloid
word-boundary count zero over 1,510 pre-existing node files, re-measured independently of the brief