BCL11A — the sickle-cell target whose binding sites lose methylation in this disease
also called BCL11A · BCL11A-XL · CTIP1 · EVI9 · ZNF856
BCL11A is a switch that decides which kind of haemoglobin a person makes, and it is already being edited to treat sickle-cell disease. In KMT2A-rearranged leukaemia the places it binds DNA lose their chemical tags.
The same thing, for a scientist
BCL11A is a zinc-finger transcription factor best known as the fetal-globin repressor now targeted therapeutically in β-haemoglobinopathies. It enters this graph by two routes: **DNA methylation loss in KMT2A-rearranged paediatric B-ALL is enriched at BCL11A transcription-factor binding sites**, and the unbiased selectivity triage places it in the top ten genes both selectively required in KMT2A-rearranged lines and quiet across normal tissue. **It is also the clearest cautionary case in that list**, because disrupting it is known to impair HSPC engraftment and erythroid maturation.
Why it is the cautionary entry in the triage
BCL11A scores well on the triage — selective in KMT2A-rearranged lines, low median expression across normal tissue. It is also a gene whose disruption has been characterised in humans and in engineered HSPCs more thoroughly than almost any other on that list, and the characterisation is not reassuring: CRISPR-Cas9 indels across its zinc-finger domains elevate fetal haemoglobin but affect normal haematopoiesis, with effects on HSPC engraftment and erythroid maturation.
That is the failure mode ana-normal-tissue-exposure warns about in its own bite_back: GTEx whole blood is dominated by mature cells, so a gene required in the stem and progenitor compartment can look quiet in an adult atlas. BCL11A is the worked example. A low normal-tissue median did not predict a benign disruption profile, and the therapeutic field had to engineer around it — base editing of specific residues rather than indels, precisely to spare the haematopoietic phenotype.
| uniprot | Q9H165 |
|---|---|
| length AA | 835 |
| gene primary | BCL11A |
| accession added | verified against live UniProt 2026-09-20; rules 66/68/69 require accession AND length_aa so verify-accessions.py can fail a swap |
| gene symbol | BCL11A |
| gene symbol note | promoted from gene_primary 2026-09-20: verify-accessions.py reads data.gene_symbol, so a gene_primary-only entry was being length-checked or id-inferred rather than symbol-asserted |
uniprot synonyms
[ "CTIP1", "EVI9", "KIAA1809", "ZNF856" ]
depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.4101,
"chronos_mean_other_leukaemia": -0.1178,
"difference": -0.2922,
"pan_essentiality_all_lines": -0.0489,
"selectivity_rank": 98,
"rank_denominator": 17728,
"provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
"how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}- BCL11A is an active therapeutic target in a different disease, and this entry is not a proposal to inhibit it in leukaemia. Its disruption is documented to affect HSPC engraftment and erythroid maturation.
- The KMT2A link here is enrichment of methylation loss at BCL11A BINDING SITES. That is not evidence that BCL11A protein or activity is altered in this disease.
- This is the worked example of why a low GTEx normal-tissue median is not a safety signal: whole blood is mature cells, and the stem and progenitor requirement is invisible to it.
- Is BCL11A expression or activity actually changed in KMT2A-rearranged B-ALL, as opposed to its motifs sitting in differentially methylated enhancers? The cited study cannot distinguish these.
- Does the BCL11A dependency in the 11-line panel survive a lineage split? It is a B-lineage factor and the panel is lineage-mixed.
- Do the neurodevelopmental-mutation carriers with normal blood counts argue that partial BCL11A loss is tolerated in humans? If so the triage's favourable reading may be right after all and the engineered phenotypes are an artefact of indels.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Array-based DNA methylation profiling of KMT2A-rearranged B-ALL cells from 26 children against normal B-cell precursors identified significant methylation changes at 2,545 CpG loci, influenced by age and by the translocation partners AFF1 and MLLT1. Methylation loss was enriched at enhancers and at transcription-factor binding sites including BCL11A, EBF and MEF2A.
DNA methylation profiling of pediatric B-cell lymphoblastic leukemia with KMT2A rearrangement identifies hypomethylation at enhancer sites · Pediatric Blood & Cancer 2017What this evidence cannot show
Abstract read on 2026-09-20; full text not read. **This is enrichment of methylation loss at BCL11A BINDING SITES, not a statement about BCL11A expression, protein level or dependency** — a motif-level enrichment can arise from chromatin opening at loci that happen to carry the motif, with no change in the factor itself. 26 children, array-based rather than sequencing-based, and the comparator is normal B-cell precursors rather than other leukaemias.
Evidence that argues against this (1)
- Transcription-factor binding-site enrichment in differentially methylated regions is among the least specific results in epigenomics: BCL11A, EBF and MEF2A are all B-lineage factors whose motifs are expected at B-cell enhancers, so finding them enriched at enhancers losing methylation in a B-lineage leukaemia may restate the lineage rather than identify a driver. Oncofusion knowledge graph (internal analysis) 2026
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.analysis
DepMap gene effect in the 11 Cellosaurus-annotated KMT2A-rearranged leukemia lines is -0.410 against -0.118 in 43 other leukemia lines, a difference of -0.292, ranking 98 of 17,728 protein-coding genes scanned; mean effect across all lines is -0.049, so it is not pan-essential. GTEx v8 gives a whole-body median of 1.1 TPM across 54 tissues, a maximum of 10.8 TPM across brain, heart, blood, liver/kidney and endocrine tissue, and a peak of 15 TPM in Skin_Not_Sun_Exposed_Suprapubic.
Selectivity against normal-tissue exposure: crossing the 17,728-gene KMT2A-rearranged dependency scan with GTEx · Oncofusion knowledge graph (internal analysis) 2026What this evidence cannot show
Selectivity read from the cached 17,728-gene scan on 2026-09-20 and expression queried from the GTEx API the same day; neither was recomputed here. **Eleven cell lines, none infant-derived**, carry the selectivity axis — the graph's standing weak spot — and GTEx is adult post-mortem tissue while the patients are infants. mRNA is not protein and neither is dependency.
Evidence that argues against this (1)
- The triage's favourable reading of BCL11A is contradicted by direct experiment. Disrupting BCL11A-XL zinc-finger domains with CRISPR-Cas9 elevates fetal globin but affects HSPC engraftment and erythroid maturation, which is why the field moved to base editing of specific residues. A low adult normal-tissue median did not predict a benign disruption profile. Molecular Therapy 2024
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Disrupting BCL11A-XL by CRISPR-Cas9 indels across its ZnF4, ZnF5 and ZnF6 domains prevents binding to the HBG1/2 promoters and elevates fetal haemoglobin, but affects normal haematopoiesis including HSPC engraftment and erythroid maturation; base editing of specific residues produced far fewer such effects. Patients with neurodevelopmental BCL11A zinc-finger mutations have elevated HbF with normal haematological parameters.
Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression · Molecular Therapy 2024What this evidence cannot show
Abstract read on 2026-09-20; full text not read, so the magnitude of the engraftment and maturation effects is not recorded. The context is β-haemoglobinopathy therapy in HSPCs, not leukaemia, and the target is the BCL11A-XL isoform specifically.
Evidence that argues against this (1)
- The human genetic evidence cuts the other way and is the stronger of the two: people carrying BCL11A zinc-finger mutations have elevated HbF **with normal haematological parameters**. That is a natural experiment in lifelong partial loss of function with no blood phenotype, which argues the engineered indel effects are a property of the editing rather than of losing the protein. Molecular Therapy 2024