CBS (P35520) - the largest fall in the whole panel (-4.07), a token that collides with Cajal bodies AND CTCF binding sites, and a germline phenotype whose hallmark is thrombosis

This is real experimental data — atoms placed by crystallography or cryo-EM, deposited by the people who did the experiment.

• **Homocystinuria from CBS deficiency has thromboembolism among its defining clinical features, and asparaginase - already backbone therapy in this disease - has thrombosis among its dose-limiting toxicities.** A menin inhibitor drops CBS 4.07 log2 in leukaemic cells. This graph's standing hypothesis proposes combining a menin inhibitor WITH asparaginase; if CBS suppression is systemic rather than blast-restricted, that combination stacks two prothrombotic mechanisms in infants, and nobody has measured plasma homocysteine in a menin-inhibitor trial.
• **The bite-back is a hypothesis about a laboratory value, not an established drug effect.** Plasma homocysteine is set largely by the liver, and a transcript fall in leukaemic blasts says nothing about hepatic CBS. It is cited here because it is cheap to check and because the consequence if true is serious, not because it is shown.
• **CBS is also fetally expressed in brain, liver and kidney**, and its germline deficiency causes intellectual disability, ectopia lentis and a Marfanoid skeleton. Any transsulfuration-directed intervention in an infant inherits that phenotype list.
• **Do not cite the -4.07 as this beat's strongest number.** It is the largest and the least secure: one platform, a modest baseline, three array probes at background in the same cell line, and a near-floor baseline in the replication arm. PHGDH's -3.24 is better supported on every axis.

1. Is plasma homocysteine raised in patients on a menin inhibitor? CBS clears homocysteine, its transcript falls 4.07 log2 in leukaemic cells, homocystinuria's hallmark is thrombosis, and asparaginase in the same protocol also causes thrombosis. Plasma homocysteine is a routine assay and could be added to an existing menin-inhibitor trial at negligible cost. This is the single most actionable item in this beat.
2. Which platform is right about CBS in RS4;11? The 3-prime-end assay says 5.97 log2 CPM and detected; all three array probes say background. The panel's largest fold change rests on the answer, and a qPCR or a transcript-variant-aware realignment settles it.
3. Does an H3K4me3 or H3K79me2 mark change at the CBS locus under a menin inhibitor? CBS has the second-largest menin-selective margin in the panel and no chromatin measurement anywhere, so it is the second locus to add to the ChIP after PHGDH.
4. Why is CBS the only serine-arm gene that responds in MOLM13? It is the exception to this beat's second finding, and either it is reached by a different input from the rest of the arm or the MOLM13 null has a gene-by-gene explanation rather than a programme-level one.

1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   On a pre-registered panel CBS shows the largest fall in the panel: RS4;11 day 7 VTP-50469 330 nM -4.07 from a detected baseline of 5.97 log2 CPM against EPZ5676 -2.60 (margin -1.47, 64% reproduced), day 2 -1.86 (46% of the day-7 effect), MOLM13 -1.02 from a detected baseline of 5.62 - the only serine-arm gene to pass 1 log2 there - and MV4;11 -1.89 against SGC0946 -0.84 from a baseline of 2.11; while on the GPL570 array all three probes are below the 6.0 log2 RMA floor in RS4;11 (4.83, 4.07, 3.86) and in REH (4.84, 3.85, 3.92) but two are well expressed in SEM (8.68 falling -0.87, 9.78 falling -1.09 under MI-2-2), the largest MI-2-2 effect on any serine gene in any line in this beat.

   analyses/q109-is-the-serine-collapse-downstream-of-atf4-or-parallel - panel declared to disk before any expression value was read and loaded by run.py; GSE127506+GSE127508, GSE63664 (every probe, own baseline) and GSE260456 · this repository 2026
   ▸What this evidence cannot show

   One line per platform, single doses, NO dose-response, n=2-3 per arm, day 7 of continuous exposure so arrest is a competing explanation. No series records the amino-acid composition of the medium, and this is an amino-acid-response panel. MI-2-2 in the array arm is the WEAK compound, so the REH wild-type contrast has little dynamic range. The headline -4.07 rests on ONE platform in a line whose array probes say CBS is at background, and nothing in these data resolves the disagreement. The MV4;11 baseline of 2.11 log2 CPM is close to the 1.0 floor so that arm's magnitude is unreliable. REH is below floor on all three probes so there is no usable KMT2A-wild-type control for CBS. Confidence is graded moderate rather than established for exactly these reasons, unlike the other genes in this tranche.

   ▸Evidence that argues against this (1)

   • A very large fold change from a modest baseline on a single platform, in a gene the other platform reads as unexpressed in the same cell line, is the profile of a measurement artefact rather than of the panel's strongest biological signal. The prior beat's MV4;11 replication reported CBS at -1.89 against RS4;11's -4.07 and attributed the gap to exposure duration; a platform or transcript-variant explanation is at least as likely and was not considered there. this repository 2026
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   CBS DepMap gene effect is mean -0.0256, median -0.0133, with 0.4% of 1,258 screens below -0.5 and a leukaemia mean of -0.0786 over 57 screens, with all 29 tissue blocks flattened and approvedSymbol read back as CBS.

   Open Targets Platform GraphQL target.depMapEssentiality, all 29 tissue blocks flattened, panel-maximum payload guard PASS at 1,258 screens; analyses/q109-serine-one-carbon-depmap-dependency/results.json · Open Targets / DepMap 2026
   ▸What this evidence cannot show

   Rule 83: the payload carries NO release identifier, so depmap_release is recorded as null and absolute values drift quarterly; the cross-gene contrast is the durable part. Leukaemia screens are matched on the payload's own diseaseFromSource string against four substrings and are NOT split by KMT2A status. Rule 84: no median-split proportion is reported - the percentage is against an absolute -0.5 threshold. A CRISPR knockout in cysteine- and serine-replete medium understates a biosynthetic dependency. Transsulfuration is the route by which a cell makes its own cysteine, and standard culture medium supplies cystine, so this is close to the least informative possible condition in which to knock out CBS.

   ▸Evidence that argues against this (1)

   • The cysteine-supply context makes this null nearly uninterpretable, and the opposing literature is explicit about it: a targetable FTO/SLC7A11/CBS/CTH axis is reported to control cysteine metabolism, growth and survival in non-small-cell lung cancer, i.e. the transsulfuration enzymes matter when cystine import is limited. SLC7A11, the cystine importer, is in this beat's panel and is the ONE gene whose compound-selectivity is inverted (+0.13 under the menin inhibitor, -1.84 under the DOT1L inhibitor), which is an unexplained result sitting directly on this axis. Kuganesan N et al. 2026
3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProt reviewed human record P35520 (CBS_HUMAN) has primary gene name CBS with no synonyms, length 551 aa, NINETEEN PDB cross-references, catalyses the first step of transsulfuration in which the hydroxyl of L-serine is displaced by L-homocysteine to form L-cystathionine - the catabolic route eliminating L-methionine and the toxic metabolite L-homocysteine - and also produces hydrogen sulfide; is annotated Cytoplasm (ECO:0000269, PubMed 17087506 and 23981774) and Nucleus (ECO:0000269, PubMed 17087506); is strongly expressed in adult liver and pancreas with some expression in heart and brain and weak expression in lung and kidney, and IN THE FETUS is expressed in brain, liver and kidney; and records cystathionine beta-synthase deficiency, whose untreated clinical features include myopia, ectopia lentis, intellectual disability, skeletal anomalies resembling Marfan syndrome and THROMBOEMBOLIC EVENTS, with increased urinary homocystine and methionine.

   UniProtKB entry P35520 (CBS_HUMAN), Cystathionine beta-synthase · UniProt Consortium · UniProt 2026
   ▸What this evidence cannot show

   Resolved 2026-09-22 with gene_exact:CBS AND organism_id:9606 AND reviewed:true; exactly one reviewed row, gene_primary and length read back - which is notable given how badly the SYMBOL collides in the literature: the accession query is clean where the text query is not. Rule 91: neither localisation paper was opened, so both ECO:0000269 statements are recorded as UniProt's pointers. The disease description is a curated summary; the GeneReviews chapter is PMID 20301697, verified bibliographically and not read. The nine PDB entries were NOT fetched and no structural claim is made from them.

   ▸Evidence that argues against this (1)

   • Homocystinuria's thrombotic risk is driven by accumulated homocysteine, which is what a CBS-deficient cell fails to clear. A cell-autonomous transcript fall in leukaemic blasts is not the same as systemic CBS deficiency: the liver sets plasma homocysteine, and a menin inhibitor's effect on hepatic CBS is unknown and unmeasured. The bite-back is a hypothesis about a measurable laboratory value, not an established drug effect, and it should be cited as one. Sacharow SJ et al. 1993
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   PubMed 2026-09-22, one tag per term with translations read back: CBS[tiab] returns 11,871 records; CBS[tiab] AND the eight-operand KMT2A-fusion set returns 3, and all three titles were opened and ALL THREE ARE FALSE POSITIVES - PMID 12686606 matches on CBs meaning Cajal bodies, PMID 35180428 matches on CBSs meaning CTCF binding sites, and PMID 30727486 is a Phytophthora plant-pathology paper - so the genuine fusion-scoped count for cystathionine beta-synthase is ZERO; and CBS[tiab] AND the nine-operand menin/menin-inhibitor set returns 0.

   NCBI E-utilities esearch against PubMed, 2026-09-22, fusion operand set (KMT2A[tiab] OR MLL[tiab] OR "MLL-AF4"[tiab] OR "KMT2A::AFF1"[tiab] OR "MLL-rearranged"[tiab] OR "t(4;11)"[tiab] OR "MLL-AF9"[tiab] OR "MLL-ENL"[tiab]), each term separately tagged and every cytogenetic term quoted · PubMed 2026
   ▸What this evidence cannot show

   The 11,871-record total is a positive count of a contaminated token and should not be quoted as 'the CBS literature'. Only the three fusion-scoped records were opened; the menin-scoped zero was not audited further than its count. This is a bibliographic bound on titles and abstracts, and the contamination means a genuine CBS-in-KMT2A paper could also be hiding inside the 11,871 without the fusion operands appearing in its abstract.

   ▸Evidence that argues against this (1)

   • Two of the three contaminants are core vocabulary of THIS project - Cajal bodies appear in its subnuclear-localisation work and CTCF binding sites in its CTCF adjudication beat - so the contamination rate for the token CBS is higher in this corpus's subject area than it would be elsewhere. That makes any CBS text search in this project unusually unsafe, and data/symbol-collisions.json currently has no CBS row. this repository 2026

• ← supportsNo menin-inhibitor trial measures homocysteine or any amino-acid endpoint across 57 records - while a recruiting infant-ALL trial already gives PEG asparaginase and ziftomenib together

  CBS falls 4.07 log2 under menin inhibition, the largest fall in the serine panel, and germline CBS deficiency causes homocystinuria with thromboembolism - the gap this entry measures is the assay that would detect it

• part of →CTH (P32929) - gene_exact returns TWO reviewed records and the second is VSIG2, a third instance of rule 62 on the same symbol the Ensembl resolver already got wrong

  CBS and CTH are the two steps of transsulfuration; CBS -4.07 and CTH -1.57 in RS4;11 day 7

• confers resistance to →Native E. coli asparaginase - the second-largest in-vitro resistance signal in infant ALL, and a different product from the pegylated one four doses later

  bite-back: CBS deficiency causes homocystinuria whose hallmark is thromboembolism, and asparaginase has thrombosis among its dose-limiting toxicities - the combination this graph proposes would stack two prothrombotic mechanisms

• depends on →MEN1 / menin — the adaptor the fusion cannot work without

  largest fall in the panel (-4.07) with the second-largest menin-selective margin (-1.47); no chromatin measurement at the locus in any system

• related to →KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3)

  the only serine-arm gene to move past 1 log2 in MOLM13 (-1.02), and therefore the exception to this beat second finding

• ← supportsThe serine/one-carbon arm is NOT a pure ATF4 output: it is menin-selective where the ISR arm is compound-independent (median margin -0.55 vs -0.02, p=0.011), and it is ABSENT in KMT2A::MLLT3 AML where the ISR arm is present

  largest fall in the panel and second-largest menin-selective margin, with a platform disagreement recorded