FOXP1 - the forkhead repressor that licenses the pro-B to pre-B transition and blocks apoptosis with NF-kB, sitting at a 105x MLL1-N bin in a leukaemia whose defining lesion is a pro-B arrest

No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.

• If FOXP1 turns out to be a dependency in KMT2A::AFF1, targeting it means suppressing the transcription factor that normal B-cell development requires at exactly the same stage. The on-target consequence in a healthy compartment is a pro-B-to-pre-B block - i.e. the drug would reproduce the disease's own defining lesion in the patient's remaining normal B lymphopoiesis.
• FOXP1's anti-apoptotic mechanism runs partly through Bcl-xL, which venetoclax does not inhibit. A FOXP1-high blast would therefore be a candidate venetoclax non-responder for a reason invisible to BH3 profiling that scores BCL2 dependence, and this graph's venetoclax content does not currently carry that route.
• FOXP1 is required in lung epithelium, cardiac muscle, spinal motor neurons, monocytes and hair-follicle stem cells. Any systemic FOXP1-directed agent has a toxicity surface spanning five organ systems with published knockout phenotypes in each, which is an unusually well-documented reason not to pursue it as a direct target.

1. Is FOXP1 up or down in KMT2A::AFF1 blasts relative to normal pro-B cells? The two published FOXP1 biologies - licensing the pro-B to pre-B transition, and blocking apoptosis with NF-kB - predict opposite signs for a leukaemia arrested at pro-B, and public expression data can answer it without new material. Until it is answered, FOXP1's presence in this beat is an observation and not an argument.
2. Does FOXP1 expression move under a menin inhibitor in KMT2A::AFF1? Its promoter loses half its MLL1-N-reactive share under VTP-50469 (0.509) while menin leaves completely (0.052), which is a pattern with no interpretation attached until transcript data is put beside it.
3. If FOXP1 supports Bcl-xL rather than BCL2, is the FOXP1 axis a venetoclax-RESISTANT anti-apoptotic route in this disease? This graph reasons extensively about venetoclax and BCL2 priming, and BCL-xL is outside venetoclax's selectivity.
4. Should the symbol-collision registry carry a FOXP-family row? FOXP1-4 heterodimerise through a shared leucine zipper, FOXP3 dominates a loose search, and FOXP1 acts cooperatively with FOXP4 - so a family-level search is not a gene-level search, and the registry has no row for any of them.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   FOXP1 is Q9H334 (FOXP1_HUMAN), 677 aa, with a C2H2-type zinc finger at 306-331, a FoxP leucine-zipper domain at 332-372, a forkhead DNA-binding domain at 465-555 and a CTBP1-binding region at 382-386; it is nuclear, is a transcriptional repressor, is an essential transcriptional regulator of B-cell development, represses pro-apoptotic genes and cooperates with NF-kB signalling to promote B-cell expansion, regulates CSF1R in monocytes with NCOR2 as corepressor, negatively regulates T follicular helper differentiation, and a distinct isoform expressed in embryonic stem cells has its own DNA-binding preference.

   UniProtKB Q9H334 (FOXP1_HUMAN), Forkhead box protein P1 · UniProt Consortium · UniProt 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-23 via gene_exact:FOXP1 AND organism_id:9606 AND reviewed:true, which returned exactly ONE reviewed record, so rule 62 does not fire. data/symbol-collisions.json (208 rows) word-boundary grepped for FOXP1 before the first query: no row. NOTE the family collision hazard the registry does not yet carry: FOXP1, FOXP2, FOXP3 and FOXP4 are paralogues that heterodimerise through the same leucine zipper, FOXP3 is the Treg master gene and dominates any loose search, and FOXP1 acts cooperatively with FOXP4 in lung epithelium - so a FOXP-family search is NOT a FOXP1 search. Per rule 91 the papers UniProt cites were not opened.

   ▸Evidence that argues against this (1)

   • UniProt's FUNCTION block for FOXP1 is a list of eleven largely unrelated tissue functions - lung epithelium, cardiac muscle, spinal motor neuron columns, midbrain dopamine identity, hair-follicle stem cell quiescence, angiogenesis, androgen receptor signalling, monocyte differentiation, T follicular helper cells, B cells and ESC pluripotency. A transcription factor with that breadth has no default behaviour, and importing any one of these functions into a leukaemic pro-B cell without a measurement in that cell is unwarranted. Nat Immunol 2006
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   HGNC assigns FOXP1 (HGNC:3823, 'forkhead box P1') the primary Ensembl gene id ENSG00000114861, cytoband 3p13 and UniProt Q9H334, with alias symbols QRF1, 12CC4, HSPC215 and hFKH1B and no previous symbol; Ensembl places the gene at GRCh37 chr3:71,003,844-71,633,140 and GRCh38 chr3:70,954,693-71,584,009, both on the MINUS strand.

   HGNC record HGNC:3823 (FOXP1) and Ensembl gene ENSG00000114861 on GRCh37 and GRCh38 · HUGO Gene Nomenclature Committee; Ensembl · genenames.org / Ensembl 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-23 and resolved before any sentence using them was written. No previous official symbol, so rule 69 does not apply. The MINUS strand is load-bearing for reading the Q118 bin and is stated here for that reason (see E8).

   ▸Evidence that argues against this (1)

   • An 'absent' alias list is weaker evidence than it looks. HGNC records four aliases for FOXP1 and no previous symbol, which this entry uses to argue that the symbol-based literature bound is not undercounting - but a gene whose paralogues heterodimerise with it through a shared leucine zipper can be discussed under a family name in a title, and no HGNC field records that. The registry has no FOXP-family row, which is itself a gap this entry names. UniProt Consortium 2026
3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   Absence of Foxp1 causes a profound defect in early B-cell development, with decreased expression of all B-lineage genes in B220+ fetal liver cells and a block in the transition from pro-B cell to pre-B cell involving diminished expression of Rag1 and Rag2; Foxp1 binds the Erag enhancer and controls V(D)J recombination of the immunoglobulin heavy-chain gene in a B-cell-lineage-specific way.

   Foxp1 is an essential transcriptional regulator of B cell development · Hu H, Wang B, Borde M, Nardone J, Maika S, Allred L, et al. · Nat Immunol 2006
   PMID 16819554DOI
   ▸What this evidence cannot show

   Abstract-level read; the full text was not opened this session. MOUSE germline knockout. The pro-B-to-pre-B block described here is a developmental arrest in a normal animal, which is a different object from the pro-B arrest of a KMT2A::AFF1 blast, and this entry does not claim they share a mechanism - only that they are at the same stage, which is what makes the comparison worth making.

   ▸Evidence that argues against this (1)

   • A conditional deletion from the pro-B stage onwards found deregulation of B-lymphocyte development and function at MULTIPLE stages rather than a single clean block, so the germline phenotype's apparent stage-specificity partly reflects when the gene was removed. A stage assignment from a germline knockout is an upper bound on specificity, not a measurement of it. Immunohorizons 2019
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   FOXP1 directly represses a set of seven pro-apoptotic genes - the BH3-only proteins BIK and Harakiri, the p53-regulatory proteins TP63, RASSF6 and TP53INP1, and AIM2 and EAF2 - whose low expression is associated with poor survival in DLBCL patients; FOXP1 promotes the expansion of primary mature human B cells by inhibiting caspase-dependent apoptosis without affecting proliferation, and it is dependent upon and cooperates with NF-kB signalling to promote B-cell expansion and survival.

   FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-kB to promote survival of human B cells · van Keimpema M, Grüneberg LJ, Mokry M, van Boxtel R, Koster J, Coffer PJ, et al. · Blood 2014
   PMID 25267198DOI
   ▸What this evidence cannot show

   Abstract-level read; the full text was not opened this session. PRIMARY HUMAN MATURE B CELLS and DLBCL cell lines - not pro-B cells and not leukaemia, so the target set is established in a differentiated compartment and its relevance to a pro-B-arrested blast is an assumption. The DLBCL survival association is correlative.

   ▸Evidence that argues against this (1)

   • FOXP1 must be DOWNREGULATED for normal germinal-centre B-cell function, and it represses plasma-cell differentiation. So the same protein is required for early development, must fall during the GC reaction, and is oncogenic when it fails to fall - its effect is entirely stage-dependent, which means 'FOXP1 is anti-apoptotic in B cells' is not a statement that can be carried into a pro-B blast without measuring it there. Blood 2013
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Conditional disruption of Foxp1 in developing and mature B cells reduces numbers and frequencies of follicular and B-1 B cells and impairs T-cell-independent antibody responses; Foxp1-deficient B cells are impaired in survival despite an increased capacity to proliferate; transcriptional analysis identifies defective expression of Bcl2l1 (Bcl-xL) with Foxp1 binding in its regulatory region, and transgenic overexpression of Bcl2 rescues the survival defect and restores peripheral B-cell numbers in vivo.

   Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells · Patzelt T, Keppler SJ, Gorka O, Thoene S, Wartewig T, Reth M, et al. · Proc Natl Acad Sci U S A 2018
   PMID 29507226DOI
   ▸What this evidence cannot show

   Abstract-level read; the full text was not opened this session. MOUSE conditional knockout, MATURE B cells. The BCL2 rescue is transgenic overexpression, which demonstrates sufficiency of an anti-apoptotic signal to restore numbers and not that Bcl-xL is the only mediator.

   ▸Evidence that argues against this (1)

   • This graph has no gene-bcl2l1 entry, so the specific anti-apoptotic effector named here cannot be linked, and the nearest node - gene-bcl2 - is a different protein with a different inhibitor profile. Venetoclax does not inhibit BCL-xL, so a FOXP1-Bcl-xL dependency would be a BCL2-inhibitor-RESISTANT anti-apoptotic axis, not a supporting argument for the venetoclax content this graph already holds. Proc Natl Acad Sci U S A 2018
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   PAX5-FOXP1, arising from t(3;9)(p13;p13), is a rare but recurrent and non-random translocation in both childhood and adult B-cell acute lymphoblastic leukaemia, proposed to contribute to leukaemogenesis by blocking differentiation of haematopoietic cells into mature B cells; FOXP1 is separately reported as a novel ABL1 fusion partner in acute lymphoblastic leukaemia.

   FOXP1 and PAX5 are rare but recurrent translocations partners in acute lymphoblastic leukemia · Put N, Deeren D, Michaux L, Vandenberghe P · Cancer Genet 2011
   PMID 21962897DOI
   ▸What this evidence cannot show

   Abstract-level read; the source is a SINGLE CASE REPORT (a 57-year-old man with B-ALL) that positions itself as the fifth reported PAX5-FOXP1 case. 'Recurrent' therefore rests on five cases across two age groups, and the leukaemogenic mechanism ('may contribute by blocking differentiation') is the authors' proposal, not a measurement. The ABL1-FOXP1 claim is from a separate report (PMID 21391972) seen at title level only and is named, not characterised.

   ▸Evidence that argues against this (1)

   • Five cases is not a frequency, and a fusion partner list assembled from case reports is shaped by which cytogenetic abnormalities get published. This graph's own epidemiology entries repeatedly find that partner-level claims built on small case series do not survive registry-scale analysis. Iqbal Lab oncofusion knowledge graph 2026
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   In RS4;11 (KMT2A::AFF1) the hg19 2 kb bin chr3:71,630,000 reaches 105.2x the MLL1-N track's own genome median and is in the top thirty bins genome-wide; under VTP-50469 its MLL1-N within-sample share ratio is 0.509 and its MENIN share ratio is 0.052.

   Q118 re-analysis of GSE127507, instrument B: 2 kb genome-wide bins from the deposited .deduped.tdf files (RS4;11 MLL1n GSM3635695/96, MENIN GSM3635693/94, input GSM3635699); analyses/q118-menin-at-the-human-index-fusion/results-instrumentB.json, run 2026-09-23 · Iqbal Lab oncofusion knowledge graph 2026
   ▸What this evidence cannot show

   THE MEASUREMENT THAT NAMED THIS GENE IS NOT FUSION-SPECIFIC. The track is MLL1n, Bethyl A300-086A, an MLL1 N-TERMINUS antibody whose epitope is retained in KMT2A::AFF1, so it reads fusion and wild-type MLL1 together at a masking factor the same beat measured as 3.54-4.00x; every statement from it is about MLL1-N-reactive material, never about the fusion. n = 1 per antibody per condition - GSE127507 has no replicate - and the depositors measured a Drosophila spike-in and deliberately did not apply it, so cross-condition figures are within-sample shares. A share ratio of 0.509 is MID-RANGE within the top thirty (which spans 0.091 to 4.036) and is therefore the least informative kind of value this measurement produces: it neither holds nor collapses.

   ▸Evidence that argues against this (1)

   • The MENIN share ratio at this bin is 0.052, i.e. menin leaves as completely as it does everywhere in the held set, while MLL1-N halves. A gene whose menin signal collapses and whose MLL1-N signal partially persists is indistinguishable from a wild-type MLL1 site, which is the single most likely explanation for a bin at a housekeeping-adjacent B-lineage transcription factor promoter. Iqbal Lab oncofusion knowledge graph 2026
8. E8strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   FOXP1 is on the MINUS strand, so its transcription starts are at the high-coordinate end of the gene: on GRCh37 the nearest starts to the bin centre chr3:71,630,000 are ENST00000498154 at 71,631,104 (1,104 bp), ENST00000493089 at 71,632,904, ENST00000318779 at 71,633,090 and ENST00000318789 at 71,633,140 (3,140 bp). The bin is therefore at the FOXP1 promoter region, not deep in the gene body as a naive comparison against the gene's `start` coordinate would suggest.

   Ensembl GRCh37 REST: lookup/id/ENSG00000114861?expand=1, per-transcript start coordinates and strand · Ensembl · Ensembl GRCh37 archive 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-23, resolved from a stable gene id to transcript coordinates rather than by a name lookup. Ensembl gene models, not experimentally mapped start sites in a leukaemic cell. Two of the four nearest starts are processed transcripts rather than protein-coding, and a 2 kb bin cannot distinguish transcripts 2 kb apart, so 'the promoter region' is the strongest claim the resolution supports.

   ▸Evidence that argues against this (1)

   • The naive containment check on this gene initially read the bin as sitting 626 kb 'into' FOXP1 - an intragenic signal - because it compared the position to the gene's low-coordinate `start`. That reading is wrong and it is the kind of wrong that passes review, which is why the per-transcript resolution is recorded as evidence rather than left implicit. Ensembl GRCh37 archive 2026
9. E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   Bounded literature counts, 2026-09-23: FOXP1[tiab] 1,073; FOXP1[tiab] AND KMT2A[tiab] 4 (none about a fusion-target relationship - optical genome mapping in AML, a salivary-gland tumour panel, a congenital-heart connectome study and an autism corticostriatal review); FOXP1[tiab] AND MLL[tiab] 2; FOXP1[tiab] AND leukemia[tiab] 39; FOXP1[tiab] AND "acute lymphoblastic"[tiab] 10; FOXP1[tiab] AND "pro-B"[tiab] 4; FOXP1[tiab] AND "B cell development"[tiab] 18; FOXP1[tiab] AND "infant"[tiab] 1 (a plasticiser-and-autism study); FOXP1[tiab] AND "MLL-AF4"[tiab] 0.

   PubMed esearch via scripts/pubmed_safe.py, 2026-09-23 · Q119-genes-the-measurement-named · NCBI PubMed 2026
   ▸What this evidence cannot show

   Bounded by TITLES AND ABSTRACTS only (rule 80). One tag per term, no parenthesised group (rule 94); every querytranslation was read back and each expanded to "TERM"[Title/Abstract]. The KMT2A, pro-B, acute-lymphoblastic, B-cell-development and infant result sets WERE read at title level and are characterised above; the 39 leukemia records were not. This is the cleanest genuine absence in the beat: FOXP1 has a large literature, a large leukaemia literature, and NOTHING connecting it to a KMT2A fusion.

   ▸Evidence that argues against this (1)

   • A bound on titles and abstracts is especially weak for a transcription factor that appears in expression signatures. FOXP1 could be a well-known component of the KMT2A::AFF1 expression programme in a supplementary table of a paper titled after something else, and none of these queries would see it - which is exactly how rule 80 was learned. NCBI PubMed 2026

• regulates →The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there

  Foxp1-null blocks the pro-B to pre-B transition with Rag1/Rag2 down and the Erag enhancer unbound - the same stage at which KMT2A::AFF1 blasts are arrested

• expressed in →Pro-B cell — the stage at which KMT2A::AFF1 leukaemia is arrested, and the phenotype the diagnosis is made on

  required in B220+ fetal liver pro-B cells for expression of all B-lineage genes

• depends on →RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin

  FOXP1 is dependent upon and cooperates with NF-kB signalling to promote B-cell expansion and survival

• regulates →The apoptotic priming state — KMT2A-rearranged infant ALL is the one childhood ALL subgroup that is BCL-2-dependent rather than BCL-XL-co-dependent, and BH3 profiling is how that was measured

  directly represses BIK, HRK, TP63, RASSF6, TP53INP1, AIM2 and EAF2 and supports Bcl-xL - an anti-apoptotic axis that venetoclax does not cover

• fuses with →PAX5 - the most frequently hit non-KMT2A gene in infant KMT2A-rearranged ALL, and it is a deletion in one allele, not a mutation

  PAX5::FOXP1 from t(3;9)(p13;p13), a rare but recurrent B-ALL translocation proposed to block B-cell differentiation

• supports →Instrument check: the top thirty RS4;11 MLL1-N 2 kb bins recovered from a deposited .tdf are JMJD1C (259x the genome median), ZMYND11, BAHCC1, CDK6, MYB, RUNX2, IGF2BP2, FOXP1, SATB1 and ARID1B - canonical KMT2A::AFF1 targets, annotated only against the series' own RefGene windows

  the entry that named this gene; the minus-strand resolution here shows its bin is at the FOXP1 promoter, not in the gene body

• related to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)

  105.2x MLL1-N-reactive bin at its promoter in RS4;11, share ratio 0.509 under VTP-50469 - NOT a fusion-specific measurement and mid-range among the top thirty