Oncofusion

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Explainerstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q26-mllt1-control-arm

KOPN-8 (CVCL_1866): the field's default KMT2A::MLLT1 line, and its fusion protein has no YEATS domain

also called KOPN8 · KOPN-8 · CVCL_1866 · ACH-001106 · DSMZ ACC-552

KOPN-8 is the cell line most papers reach for when they want to study this fusion, and it comes from a three-month-old girl. It turns out its fusion protein is missing the acetyl-reading module that 84% of patients keep, so most of what the field knows about this fusion comes from an unrepresentative version of it.

The same thing, for a scientist

Cellosaurus CVCL_1866 records KOPN-8 as a female, 3-month-old, Japanese, childhood B acute lymphoblastic leukaemia line derived from peripheral blood, carrying a KMT2A + MLLT1 gene fusion, KRAS p.Gly12Asp heterozygous and TP53 p.Arg248Gln heterozygous, microsatellite stable, DepMap ACH-001106, DSMZ ACC-552, and membership of DepMap/CCLE, COSMIC, LL-100 and the MD Anderson Cell Lines Project [E1]. It is the KMT2A::MLLT1 line in the menin-inhibitor series (MI-2, MI-503, ziftomenib, VTP-50469) and in the DOT1L-inhibitor series (EPZ004777, pinometostat) [E2][E3][E4]. The fact that reframes all of that: **KOPN-8's MLL-ENL fusion protein lacks the YEATS domain**, placing it in the 15.9% of t(11;19) patients whose breakpoint falls downstream of MLLT1 exon 2, not the 84.1% who retain the reader [E5]. Its breakpoint is therefore intra-MLLT1, so KOPN-8 is a **reciprocal-capable** line, and no publication states whether it expresses a reciprocal transcript.

Go deeper
Why the YEATS status matters more than it looks

The 2023 Leukemia study that established the 84.1% figure used KOPN-8 explicitly as its YEATS-negative comparator against HB1119 as the YEATS-positive line, and found HB1119 more sensitive to the YEATS inhibitor SGC-iMLLT at 2 uM 5. So the two most-used human KMT2A::MLLT1 lines sit on opposite sides of a split that divides the patient population 254 to 48, and the one that is over-represented in the literature is the one representing the 48. Any claim of the form 'KMT2A::MLLT1 cells respond to X' that rests on KOPN-8 alone is a claim about the minority architecture.

What KOPN-8 has actually been used to show

Menin: the menin-MLL inhibitor MI-2 gave a GI50 of 7.2 uM in KOPN-8, the lowest of the four MLL-r lines tested in that paper (MV4;11 9.5, ML-2 8.7, MonoMac6 18) 2. KOPN-8 also appears in the MI-503 in vivo series and in the ziftomenib preclinical panel 3. DOT1L: EPZ004777 gave an IC50 of 0.62 uM (95% CI 0.49-0.79) in KOPN-8, squarely inside the MLL-r range and not an outlier 4. Pinometostat treatment-emergent resistance was generated in KOPN-8, where increased ABCB1/P-glycoprotein expression was the primary resistance mechanism 6. Note the cross-link: the DOT1L evidence for 'MLL-ENL' therefore rests substantially on a YEATS-less fusion, which matters if DOT1L recruitment is argued to depend on the reader.

Co-lesions are not decorative here

KRAS p.Gly12Asp and TP53 p.Arg248Gln, both heterozygous 1. RAS pathway mutation is the commonest co-lesion class in KMT2A-rearranged infant ALL and is itself associated with refractory disease, and TP53 R248Q is a dominant-negative hotspot. A drug-response number from KOPN-8 is a number from a RAS-mutant, TP53-mutant, YEATS-less background. That is three departures from the modal patient in one line.

Facts and figures
accessionCVCL_1866
accession verifiedfetched from https://api.cellosaurus.org/cell-line/CVCL_1866?format=txt on 2026-09-19; primary name read back as KOPN-8
depmap IDACH-001106
dsmzACC-552
fusionKMT2A::MLLT1 (MLL-ENL)
yeats domain in fusionfalse
reciprocal statusunknown; breakpoint is intra-MLLT1 (downstream of exon 2) so the line is reciprocal-CAPABLE, but no publication reports whether a reciprocal transcript is expressed
sexFemale
age at derivation3 months
populationJapanese
lineageB-cell precursor ALL
siteperipheral blood
msiMSS
doubling time h48
co lesions
[
  "KRAS p.Gly12Asp heterozygous",
  "TP53 p.Arg248Gln heterozygous"
]
panels
[
  "DepMap/CCLE",
  "COSMIC cell lines project",
  "LL-100",
  "MD Anderson Cell Lines Project"
]
drug data
{
  "MI-2_GI50_uM": 7.2,
  "EPZ004777_IC50_uM": 0.62,
  "EPZ004777_IC50_CI": "0.49-0.79"
}
How this could bite us back
  • If KMT2A::MLLT1 drug-response expectations are set by KOPN-8, they are set by the minority architecture. A YEATS-directed agent would look weaker than it is, and any agent whose effect depends on the ENL reader would be under-estimated for 84% of patients.
  • KOPN-8's KRAS G12D is an established route to menin-inhibitor-independent proliferation and to chemotherapy refractoriness, so negative combination results in this line have an alternative explanation that has nothing to do with the fusion.
Still open
  1. Does KOPN-8 express a reciprocal MLLT1::KMT2A transcript? Its breakpoint is intra-MLLT1 so one is possible, and a single RT-PCR would answer a question that has stood since 1992.
  2. At which MLLT1 exon does KOPN-8's fusion join? 'Lacks the YEATS domain' is compatible with exon 6 or exon 7, and the distinction determines how much of the disordered region is present - which is the confound the YEATS-deletion mouse experiments explicitly flag.
  3. How much of this fusion's published pharmacology should be re-run in a YEATS-containing line? KOPN-8 represents 15.9% of patients and carries most of the menin and DOT1L data for this partner.
Every source behind this entry (6)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Cellosaurus accession CVCL_1866 records KOPN-8 as a female, 3-month-old, Japanese, childhood B acute lymphoblastic leukaemia line (NCIt C9140 and C80342, ORDO Orphanet_585918) derived in situ from peripheral blood, carrying a KMT2A + MLLT1 gene fusion (KMT2A-MLLT1 / MLL-MLLT1 / MLL-ENL), KRAS p.Gly12Asp (c.35G>A) heterozygous and TP53 p.Arg248Gln (c.743G>A) heterozygous, microsatellite stable, doubling time about 48 hours, DepMap identifier ACH-001106, DSMZ ACC-552, and membership of DepMap/CCLE, COSMIC, the LL-100 blood cancer panel and the MD Anderson Cell Lines Project.

    Cellosaurus cell line KOPN-8 (CVCL_1866) · Bairoch A, et al.; Cellosaurus · Cellosaurus (SIB) 2026
    What this evidence cannot show

    Fetched by accession on 2026-09-19 and the primary name read back as KOPN-8 before any field was used. This project previously recorded a cell line accession that resolved to an unrelated endometrial carcinoma, which is why the read-back is stated. Cellosaurus does not record the MLLT1 exon at which KOPN-8's fusion joins, and the fusion annotation is referenced to a panel paper rather than to a breakpoint-mapping study.

    Evidence that argues against this (1)
    • Cellosaurus's fusion annotation for this line cites the LL-100 panel paper, whose purpose was authentication and uniform sequencing across 100 lines rather than breakpoint mapping, so the junction is not established by the cited source. Quentmeier H et al. 2019
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Treatment with the menin-MLL inhibitor MI-2 gave GI50 values below 10 uM in MV4;11 (MLL-AF4, 9.5 uM), KOPN-8 (MLL-ENL, 7.2 uM) and ML-2 (MLL-AF6, 8.7 uM), and 18 uM in MonoMac6 (MLL-AF9); MI-2 and MI-3 blocked proliferation of mouse bone marrow cells transduced with MLL-AF9 and MLL-ENL with GI50 values of about 5 uM, induced differentiation in MLL-ENL transformed cells, and downregulated Hoxa9/Meis1 in them.

    Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. · Grembecka J, He S, Shi A, Purohit T, et al. · Nat Chem Biol 2012
    PMID 22286128DOI
    What this evidence cannot show

    Numbers relayed from a full-text reading (PMC3401603) performed by a delegated worker in this session; the PMID, title and DOI were independently re-fetched from PubMed esummary on 2026-09-19 by the author of this entry, but the figures were not independently re-read. MI-2 is a tool compound with micromolar potency, not a clinical menin inhibitor; a 7.2 uM GI50 is not evidence of the potency achieved by revumenib or ziftomenib.

    Evidence that argues against this (1)
    • The same group's follow-up concluded explicitly that menin-MLL inhibitors block transformation by MLL fusions in a fusion-partner-INDEPENDENT manner, so KOPN-8's position as the most sensitive line in one four-line panel should not be read as MLLT1-specific menin dependence. He S et al. 2016
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    KOPN-8 (KMT2A-ENL) is one of the human KMT2A-rearranged lines used to demonstrate menin-KMT2A dependency for ziftomenib, in a panel with MV4;11, MOLM-13, SEM and RS4;11 showing GI50 values of 4.5-28 nM and more than 100-fold selectivity over control lines, and it also appears in the MI-503 human cell line panel.

    PMID 41849234DOI
    What this evidence cannot show

    Relayed from a full-text reading (PMC13507986) by a delegated worker; PMID, title and DOI independently re-fetched 2026-09-19. The 4.5-28 nM range is reported for the panel as a whole; the KOPN-8 value is not printed separately in the text, so no MLLT1-specific potency can be quoted from it.

    Evidence that argues against this (1)
    • The clinical KMT2A-rearranged arm of the ziftomenib programme was halted over differentiation syndrome rate and severity, so preclinical potency in this line has not translated into a KMT2A-r registrational result. Wang ES et al. 2024
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In a concentration-dependent proliferation assay the DOT1L inhibitor EPZ004777 gave an IC50 of 0.62 uM (95% CI 0.49-0.79) in KOPN-8 (MLL-ENL), against 0.17 uM in MV4-11, 1.72 uM in SEM, 6.47 uM in RS4;11 (all MLL-AF4), 0.72 uM in MOLM-13 and 3.36 uM in THP-1 (MLL-AF9), and 13.9 to more than 50 uM in non-rearranged lines.

    Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. · Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, et al. · Cancer Cell 2011
    PMID 21741596DOI
    What this evidence cannot show

    Table 2 values relayed from a full-text reading (PMC4046888) by a delegated worker; PMID, title and DOI independently re-fetched 2026-09-19. EPZ004777 is the tool compound, not pinometostat. The MLL-AF4 lines span a 38-fold range among themselves, so between-line IC50 differences in this assay are not attributable to fusion partner.

    Evidence that argues against this (1)
    • The clinical DOT1L inhibitor pinometostat produced limited single-agent responses in KMT2A-rearranged leukaemia, so in vitro sensitivity in this line did not predict clinical benefit for any partner. Campbell CT et al. 2017
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Read in full text (PMC11246743): KOPN8 cells harbour MLL-ENL fusion proteins lacking the YEATS domain while HB1119 cells are driven by MLL-ENL fusion proteins containing it; 84.1% (n = 254 of 302) of t(11;19) patients retain the YEATS domain and 15.9% (n = 48) break downstream of exon 2; and greater sensitivity to the YEATS inhibitor SGC-iMLLT was detected for HB1119 than for KOPN8 at 2 uM.

    PMID 36435883DOI
    What this evidence cannot show

    Read via the PMC HTML page (route 4) after Europe PMC fullTextXML returned HTTP 500 and efetch db=pmc returned HTTP 429. The paper attributes KOPN-8's YEATS-less status to a cited reference rather than mapping the breakpoint itself, and all four human lines were sensitive to 20 uM SGC-iMLLT, which the authors note may be cytotoxic - so the discriminating observation rests on a single concentration.

    Evidence that argues against this (1)
    • MV4;11, which is KMT2A::AFF1 and has no ENL YEATS domain at all, was as sensitive as HB1119 at 2 uM, which the authors attribute to a role for WILD-TYPE ENL in leukaemic cell survival - so SGC-iMLLT sensitivity is not a clean readout of fusion-borne YEATS. Hu H et al. 2023
  6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Treatment-emergent resistance to pinometostat (EPZ-5676) was generated in five MLL-rearranged cell lines including KOPN-8, and in KOPN-8 resistant cells increased expression of the drug efflux transporter ABCB1 (P-glycoprotein, MDR1) was the primary mechanism of resistance.

    Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia. · Campbell CT, Haladyna JN, Drubin DA, Thomson TM, et al. · Mol Cancer Ther 2017
    PMID 28428443DOI
    What this evidence cannot show

    Abstract-level reading. Resistance generated in vitro by prolonged drug exposure is not the same as clinical resistance, and ABCB1 upregulation is a generic efflux mechanism with no relation to fusion biology.

    Evidence that argues against this (1)
    • The same study found different primary resistance mechanisms in the other four lines, so the KOPN-8 result is line-specific rather than a property of the KMT2A::MLLT1 fusion. Campbell CT et al. 2017
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