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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.

ASNS - the resistance gene for a backbone drug, never measured in this disease

also called asparagine synthetase · TS11 · P08243

One of the drugs every child with this leukaemia receives works by starving the cancer of a building block called asparagine, and cells become resistant by switching on ASNS, the gene that makes it. Nobody has measured ASNS in this particular leukaemia, even though it is among the most resistant to that drug.

The same thing, for a scientist

ASNS (P08243, 561 aa) synthesises asparagine, and **L-asparaginase works by exploiting low ASNS expression**; resistance emerges through **ASNS induction, mediated in part by the amino-acid stress sensor GCN2** (PMID 42241118). In KMT2A-rearranged infant ALL, asparaginase resistance is the **second-largest in-vitro effect in the whole backbone at about 12-fold** - and **the mechanism has never been measured in this disease.** The gene is named in 3 entries of this graph and had none of its own.

Go deeper
A textbook mechanism, unmeasured in the disease that most needs it

The pharmacology is clean. L-asparaginase depletes circulating asparagine, which kills cells that cannot make their own. ALL blasts characteristically express low ASNS, which is why the drug works at all, and resistance arises by inducing ASNS - a response routed in part through GCN2, the amino-acid stress sensor.

The gap is specific and large. Infant KMT2A-rearranged ALL shows roughly 12-fold in-vitro asparaginase resistance, the second-largest effect across the entire Interfant backbone after prednisolone. Nobody has measured ASNS expression, induction or GCN2 signalling in these blasts. So the graph carries a large resistance phenotype and a well-understood candidate mechanism with no measurement connecting them.

And the drug is three enzymes. Native E. coli asparaginase, pegaspargase and Erwinia crisantaspase are different proteins dosed in incommensurable units - the protocol's own equivalence is 45,000 U/m2 native to 2,500 U/m2 pegaspargase, an 18-fold ratio. Asparaginase units must never be summed across a protocol, and an ASNS result must record which enzyme was used.

Facts and figures
uniprotP08243
length AA561
gene primaryASNS
named in entries when written3
gene symbolASNS
gene symbol notepromoted 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
menin inhibition lowers asns cycle 56VTP-50469 330 nM, RS4;11, day 7: ASNS -1.72 log2. REH (KMT2A-wild-type): +0.26. MI-2-2 10 uM in RS4;11: +0.17. Predicts re-sensitisation to asparaginase; see the hypothesis entry. PubMed has ZERO records for menin AND asparaginase (parsed, run twice).
uniprot synonyms
[
  "TS11"
]
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.1597,
  "chronos_mean_other_leukaemia": -0.2126,
  "difference": 0.0529,
  "pan_essentiality_all_lines": -0.2977,
  "selectivity_rank": 14969,
  "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."
}
How this could bite us back
  • Asparaginase is a backbone drug with substantial toxicity - pancreatitis, thrombosis, hypersensitivity - given to infants. Nothing here supports changing its use; what this entry records is that the standard resistance mechanism has never been checked in the subtype with the second-largest resistance in the protocol.
  • Never sum asparaginase units across a protocol. Native, pegylated and Erwinia preparations are different proteins with an 18-fold unit ratio in the protocol's own equivalence, and a summed total is meaningless.
Still open
  1. What is ASNS expression in infant KMT2A-rearranged blasts, and does it induce under asparaginase? The single cheapest measurement this entry points to.
  2. Is the ~12-fold asparaginase resistance ASNS-mediated at all, or stromal asparagine supply?
  3. Does GCN2 signalling differ in this subtype?
Every source behind this entry (3)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Current ALL therapy exploits leukaemic cells' low expression of asparagine synthetase by using L-asparaginase to deplete circulating asparagine, and resistance can emerge through induction of ASNS, mediated in part by the amino-acid stress sensor GCN2.

    PMID 42241118DOI
    What this evidence cannot show

    Abstract fetched and read back on 2026-09-20; full text not read. **Strong as a statement of the established pharmacology, which this paper restates in order to target it.** The study covers B-ALL and T-ALL generally and **says nothing about KMT2A-rearranged or infant disease**, so it supplies the mechanism and not its measurement here. 'Mediated in part by' is the paper's own hedge.

    Evidence that argues against this (1)
    • A mechanism that is textbook across ALL need not be the operative one in a subtype with a distinct differentiation block; this graph has repeatedly found that infant KMT2A-rearranged biology diverges from ALL generally, and the in-vitro resistance profile in this disease was concluded by its own authors to track the proB immunophenotype rather than the rearrangement. Stam RW et al. 2010
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    The reviewed human UniProt record for ASNS is P08243, 561 amino acids, primary gene name ASNS, protein name asparagine synthetase (glutamine-hydrolysing), with TS11 as its sole listed gene synonym.

    What this evidence cannot show

    Fetched from the UniProt REST API on 2026-09-20 with gene_primary and length read back. Established for the database state on that date. Recorded because rules 66/68/69 require accession and length on every gene entry so a paralogue swap fails verify-accessions.py; ASNS has no close paralogue in this graph, so the defence is cheap here rather than load-bearing.

    Evidence that argues against this (1)
    • An accession verifies identity, not that the enzyme is the relevant variable. Asparaginase sensitivity depends on asparagine availability in the microenvironment as well as on the blast's own synthetic capacity, and mesenchymal stromal cells have been reported to supply asparagine to leukaemic cells - a source no ASNS measurement in the blast would capture. Claude R et al. 2026
  3. E_k56_meninmoderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    ASNS transcript falls 1.72 log2 (3.3-fold) in RS4;11, a KMT2A::AFF1 line, under the potent menin-MLL inhibitor VTP-50469 at 330 nM by day 7, and is unchanged (+0.26) in REH, a KMT2A-wild-type line. It falls as part of a coherent collapse of the whole ATF4-driven amino-acid-response and serine/one-carbon programme in the same samples: CBS -4.07, PHGDH -3.24, PSAT1 -2.40, CTH -1.57, GPT2 -1.54, MTHFD2 -1.16, SHMT2 -1.09, SLC7A5 -1.34, SLC3A2 -1.27, SLC1A5 -0.99, with ATF4 itself -0.86 and DDIT3/CHOP -1.50. The weak first-generation compound MI-2-2 does not move ASNS at all (+0.17). This is the first measurement bearing on this entry's statement that the asparaginase-resistance mechanism has never been measured in this disease - it is a transcript measurement in cell lines, not the mechanism, but it is not nothing.

    PMID 31821784
    What this evidence cannot show

    Transcript, not protein, and ASNS protein is what asparaginase sensitivity depends on. Cell lines, neither of them infant-derived. One compound, one dose, day 7, and the panel was assembled after the fact rather than pre-declared. The wild-type comparison uses the WEAK compound because no public dataset applies a potent menin inhibitor to a KMT2A-wild-type leukaemia line. And an entire biosynthetic programme falling at day 7 under an effective drug may be a consequence of arrest rather than a direct transcriptional effect.

    Evidence that argues against this (1)
    • This entry names GCN2 as the sensor mediating ASNS induction and never names ATF4, which is GCN2's canonical downstream effector and the transcription factor whose target set is what actually moved in the measurement above. That omission is why the connection between this entry and the menin literature was never made: the two halves were filed under different names for the same axis.
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