BOD1L (BOD1L1) — the top SETD1A co-dependency, and the only candidate in this cycle tested by CRISPR tiling in a KMT2A::AFF1 line

Full text read (PMC11381347), not abstract only. The KMT2A::AFF1 content is specifically the MV4-11 arm of the two CRISPR tiling screens (618 sgRNA against BOD1L, plus a SETD1A tiling screen), reported alongside MOLM-13. Every other phenotype in the paper — apoptosis, colony formation, ChIP, immunoprecipitation, the cDNA rescue — is MOLM-13, 293T or mouse. No physical BOD1L-KMT2A, BOD1L-AFF1 or BOD1L-fusion interaction is reported; BOD1L's partner throughout is SETD1A. The in vivo model is described as a mouse MLL-r leukemia model, not KMT2A::AFF1. The authors state explicitly that they could not evaluate BOD1L's role in canonical SETD1A function in this cell type, because MLL-r leukemia cells do not depend on the SETD1A SET domain.

• BOD1L's best-characterised function is in DNA repair, not transcription, and that is a liability rather than a second opportunity. SETD1A-BOD1L H3K4 methylation recruits RIF1 to double-strand breaks and directs non-homologous end joining; losing SETD1A or BOD1L allows uncontrolled resection of DNA ends, impairs end-joining of dysfunctional telomeres and abrogates class switch recombination, and in BRCA1-deficient cells restores homologous recombination and confers PARP-inhibitor resistance. A BOD1L-directed agent in a child is therefore an agent that degrades end-joining fidelity and class switch recombination at the same time as it attacks the leukemia. Bayley R et al. 2022

Cell-line provenance database, fetched and read. MV4-11 is the right fusion in the wrong lineage for this project's index population: it is an acute monocytic leukemia from a 10-year-old, not infant B-ALL. The co-occurring FLT3-ITD is a strong independent driver and a known confounder in this line, so a dependency seen in MV4-11 cannot be attributed to KMT2A::AFF1 without a second line. MOLM-13, the co-screened line, is KMT2A::MLLT3 and also FLT3-ITD positive.

• The karyotype is not the confound that matters most in a line used for a tiling screen. Ben-David et al. showed 27 strains of a single widely distributed line had diversified genetically and transcriptionally, with differential activation of expression programmes, marked differences in morphology and proliferation, and at least 75% of strongly active compounds from a 321-compound panel inactive in some strains; barcoding traced this to positive clonal selection sensitive to culture conditions. A dependency mapped in one laboratory's doxycycline-inducible Cas9 MV4-11 is a statement about that population. Nothing in the BOD1L paper or in this entry records which MV4-11 strain, at what passage, and no independent laboratory has repeated the tiling result. Ben-David U et al. 2018

Queried by this agent this cycle; the API does not state the DepMap release, so the release is unverified. This value is reported here as the objection to the entry and not as support for it. It agrees with the primary paper's own statement that BOD1L was 'classified as non-essential in all leukemia cell lines' in DepMap, so the two sources are consistent about the fact and differ only about what it means.

• The primary paper gives the mechanistic reason the genome-wide null should not be believed as a statement about dispensability: 'Perturbation effects of CRISPR-based assays are also dependent on the position of the designed sgRNA.' Their 618-sgRNA tiling screen found a strong dependency confined to the N-terminal Shg1 domain of a 3,051-residue protein. A standard library with a handful of guides spread across a gene that long will usually miss it, and C-terminal truncations leave the functional domain intact. See PubMed record PMID 38989615 for the full author list (not transcribed here) 2024

Fetched and the primary gene name read back rather than assumed, per the standing accession rule. The naming matters for retrieval: the leukemia literature says BOD1L, HGNC says BOD1L1, and BOD1 and BOD1L2 are different genes. The absence of UniProt domain features is why no residue ranges are given in data.domains: the Shg1 domain boundaries and residue W104 come from the primary paper and are not independently annotated, so putting invented coordinates into the domain viewer would be worse than leaving the lane out.

• NO PUBLISHED OPPOSITION, and the naming problem this item flags is measurable rather than hypothetical. PubMed searches run this session return BOD1L[tiab] = 14 records and BOD1L1[tiab] = 10 records (raw counts, not de-duplicated against each other and not individually title-checked), so neither symbol alone retrieves the literature and a search keyed to the HGNC-approved symbol misses part of it. What would falsify the item as written: a UniProt or HGNC revision changing the primary symbol or the canonical length from 3,051 aa; a published experimental structure or domain assignment for the Shg1 region that fixes boundaries independently of the single 2024 paper; or a second laboratory's residue numbering that disagrees with W104. None of these exists: no PDB entry and no UniProt-annotated domain is recorded for Q8NFC6, which is why this entry carries no residue ranges in data.domains and why the domain viewer cannot draw a lane for it. No citation is attached because there is nothing to cite: this note is a bounded absence plus a falsifier list, resting on the UniProt record already cited by the parent item, not a sourced fact. Uncited and unciteable look identical in this field, so it is said here explicitly (Q42 citation-integrity repair, 2026-09-20).

Abstract read, not full text. Cited here for the contrast that makes BOD1L a different kind of claim from RBBP5 and ASH2L, not as support for BOD1L. The study is mouse and the fusion is MLL-AF9, not KMT2A::AFF1; it concerns wild-type MLL1's SET domain, which KMT2A fusions do not retain in any case. It says nothing directly about SETD1A, a different SET1-family enzyme — though the BOD1L paper independently states that MLL-r leukemia cells do not depend on SETD1A SET-domain function either.

• The contrast this item is cited for depends on wild-type MLL1 being the relevant enzyme, and the later genetics says it is not. Chen et al. found endogenous MLL1 dispensable for MLL-rearranged leukaemia in independent conditional animal models, while deletion of the paralogue Mll2 alone significantly impaired survival of MLL-AF9-transformed cells, with additional Mll1 loss further reducing viability and the two collaborating through distinct pathways rather than redundantly. 'MLL1's catalysis is dispensable, so a non-catalytic handle is the interesting one' is a weaker motivation once MLL1 as a whole is dispensable: the argument for BOD1L has to be made on SETD1A's own non-catalytic function, which the primary paper supports directly, rather than on a contrast with MLL1. Chen Y et al. 2017

Queried by this agent this cycle. At 240.7 expected loss-of-function variants this is the best-powered constraint estimate of any candidate in this beat, so the low LOEUF is reliable in the direction the safety triage says to trust. As always, constraint models lifelong heterozygous germline loss and not months of partial pharmacological inhibition; MEN1 has comparable constraint and an approved, tolerated inhibitor.

• The constraint metric measures something other than what a safety triage wants to know, and its own authors define the limits. Karczewski et al. built the constraint spectrum from 125,748 exomes and 15,708 genomes, identifying 443,769 high-confidence predicted loss-of-function variants only after filtering artefacts caused by sequencing and annotation errors, and classified genes by tolerance to INACTIVATION - validated against model-organism and engineered-human-cell essentiality, not against drug tolerability. pLI 0.999999 for BOD1L1 therefore says selection has removed heterozygous null carriers over evolutionary time; it does not bound the effect of partial, reversible inhibition over months, and the entry's own comparator makes the point - MEN1 is comparably constrained and has an approved, tolerated inhibitor. Karczewski KJ et al. 2020

Abstract read in full; full text not read. Human non-haematopoietic cell lines under induced replication stress - not leukaemia, not KMT2A-rearranged (brief rule 73). The address is FUNCTIONAL and genetic, inferred from epistasis with DNA2, BLM and FBH1 and from RAD51 stability, rather than from an image of BOD1L at a fork. UniProt Q8NFC6 annotates the subcellular location as 'Chromosome' at ECO:0000269 and gives nothing finer. Note the primary gene symbol is BOD1L1, not BOD1L.

• The fork-protection function BOD1L is credited with is shared, and the same phenotype is produced by proteins with no relationship to BOD1L. Depleting SETD1A - whose H3K4 methylation at forks enables FANCD2's nucleosome chaperone activity - causes the same uncontrolled DNA2-dependent resection and the same loss of RAD51 nucleofilament stability, as does a chaperone-defective FANCD2 mutant. A BOD1L-specific subnuclear or therapeutic claim has to distinguish itself from those. Higgs MR et al. 2018

Abstract read in full; full text not read. Human non-haematopoietic cells - not leukaemia, not KMT2A-rearranged, not infant B-lineage (brief rule 73). This paper is about SETD1A and FANCD2 and does not measure BOD1L; it is cited here to establish what the pathway is, not to make a BOD1L measurement. No cell type or cell state has been measured for BOD1L in any haematopoietic system, and this entry records that as an absence rather than filling it.

• The one documented requirement of this pathway in a human haematopoietic compartment is the Fanconi phenotype - an HSPC defect driven by a p53/p21 response to replication stress, in patients carrying no fusion. That is the lineage-level explanation for why fork-protection genes matter in marrow, and it is available without invoking KMT2A. Ceccaldi R et al. 2012