Import class 5: evidence borrowed from fusions that are not KMT2A fusions at all
also called CALM-AF10 import · NUP98 import · cross-family import
Some of the mechanism in this graph comes from leukaemias driven by entirely different fusion proteins - PICALM-AF10, NUP98 fusions, or rare KMT2A partners like AF6 and EEN. These are two steps removed from the infant fusion rather than one, and the borrowing is usually deliberate and disclosed.
The same thing, for a scientist
Three of the 24 fusion-bearing entries in the audit sample (12%) rest on a system that is not a KMT2A fusion at all: **PICALM::MLLT10** for the AF10 PZP cis-resupply design, **NUP98-rearranged leukaemia** for the menin dependency comparison, and adult non-KMT2A AML for monocytic venetoclax resistance [E1][E2][E3]. A fourth group sits one step closer - rare KMT2A partners such as **MLL-AF6** [E4] and **MLL-EEN** [E5], which are KMT2A fusions but share neither partner family nor mechanism with AFF1. **This class is the best-behaved of the five.** In every sampled instance the entry names the source system explicitly, usually in its title, because a cross-family borrowing is too obvious to leave unstated. It is recorded here not because it is dangerous but because omitting it would make the audit's denominator wrong, and because it contains the one genuinely load-bearing cross-family claim in the graph: that menin dependency is not exclusive to KMT2A fusions [E2], which is simultaneously an argument for the menin interface's breadth and against its specificity.
The cross-family claim that cuts both ways
NUP98-rearranged leukaemia is menin-dependent 2. For this project's central bet that is good news and bad news in the same sentence.
Good: it shows the menin-KMT2A1 interaction is a real, load-bearing node in leukaemic transcription rather than an idiosyncrasy of KMT2A fusions, and it widens the potential indication for menin inhibitors.
Bad for specificity: if menin dependency arises in leukaemias whose driver is not a KMT2A fusion, then menin inhibition is not acting on a fusion-specific surface. It is acting on wild-type KMT2A1-menin, a complex that normal haematopoiesis also uses. That is the same conclusion the graph reaches from the wild-type-allele requirement, and it is the principal structural argument against the menin interface being a selective target rather than merely an effective one.
Why cross-family imports are safer than same-family ones
Counter-intuitively, borrowing from PICALM::MLLT10 or NUP98-NSD1 is less likely to mislead than borrowing from MLL-AF9. The distance is visible. Nobody writes 'the fusion recruits DOT1L' and silently means CALM-AF10, because the sentence would not parse; but 'the fusion recruits DOT1L through the AHD' reads perfectly well as a general statement about KMT2A fusions while being true only of two of them.
The hazardous imports are the near ones. That is an argument for weighting audit effort toward MLL-AF9 and MLL-ENL rather than toward the exotic systems that look more foreign.
| class | cross-family import |
|---|---|
| sampled instances | 3 |
| sample denominator | 24 |
| fraction PCT | 12 |
| why safer | the distance is visible in the sentence, so it is rarely left unstated |
source systems
[ "PICALM::MLLT10", "NUP98-rearranged", "non-KMT2A adult AML", "MLL-AF6", "MLL-EEN" ]
- If menin dependency is not KMT2A-specific, resistance mechanisms discovered in one fusion family will transfer to the index disease too, and the resistance literature this graph holds is mostly from myeloid KMT2A-rearranged disease.
- Widening the menin-inhibitor indication to non-KMT2A leukaemias strengthens the commercial case and weakens the argument that the drug spares normal tissue by targeting something the fusion uniquely needs.
- How many non-KMT2A leukaemias are menin-dependent? If the list keeps growing, the menin interface is a general transcriptional dependency and its apparent KMT2A specificity is a sampling artefact of who has been treated.
- Is there any mechanism established first in a non-KMT2A fusion that later proved true in KMT2A::AFF1? A single worked example would tell the graph how much cross-family borrowing is worth.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In CALM-AF10, incorporating a functional PZP domain into the fusion prevented transformation of bone-marrow haematopoietic stem and progenitor cells in vitro and in vivo, abrogated leukemogenesis and downregulated Hoxa genes.
The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations. · Klein BJ, Deshpande A, Cox KL, Xuan F, Zandian M, Barbosa K, Khanal S, Tong Q, Zhang Y, Zhang P, Sinha A, Bohlander SK, Shi X, Wen H, Poirier MG, Deshpande AJ, Kutateladze TG · Nat Commun 2021What this evidence cannot show
Identifier and abstract content verified against PubMed on 2026-09-19 during this beat's citation rebuild. PICALM::MLLT10 is not a KMT2A fusion; the design value of this result for a KMT2A experiment is feasibility and expected effect size, not mechanism. Murine HSPC transformation.
Evidence that argues against this (1)
- The PZP domain reads unmodified H3K27, so a cis-resupply result is as much a statement about chromatin state as about the fusion, and its transfer to a KMT2A fusion assumes the same chromatin context in a different disease. Deshpande AJ et al. 2014
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged leukaemia.
The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. · Heikamp EB, Henrich JA, Perner F, Wong EM, Hatton C, Wen Y, Barwe SP, Gopalakrishnapillai A, Xu H, Uckelmann HJ, Takao S, Kazansky Y, Pikman Y, McGeehan GM, Kolb EA, Kentsis A, Armstrong SA · Blood 2022What this evidence cannot show
Identifier, title, journal, year and DOI fetched from PubMed on 2026-09-19 and copied from that record; the abstract was not re-read in this cycle, so the claim is asserted at the level of the title's own statement. NUP98-rearranged disease is myeloid and is not a KMT2A fusion.
Evidence that argues against this (1)
- A menin dependency outside KMT2A-rearranged leukaemia argues that menin inhibition targets wild-type KMT2A1-menin rather than a fusion-specific surface, which weakens the selectivity case for the menin interface even as it strengthens the efficacy case. Thiel AT et al. 2010
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Responses to venetoclax plus azacitidine in older previously untreated AML correlate with developmental stage - phenotypically primitive AML is sensitive and monocytic AML is more resistant - and resistant monocytic AML has a distinct transcriptomic profile, loses BCL2 expression and relies on MCL1.
Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia. · Pei S, Pollyea DA, Gustafson A, Stevens BM, Minhajuddin M, Fu R, Riemondy KA, Gillen AE, Sheridan RM, Kim J, Costello JC, Amaya ML, Inguva A, Winters A, Ye H, Krug A, Jones CL, Adane B, Khan N, Ponder J, Schowinsky J, Abbott D, Hammes A, Myers JR, Ashton JM, Nemkov T, D'Alessandro A, Gutman JA, Ramsey HE, Savona MR, Smith CA, Jordan CT · Cancer Discov 2020What this evidence cannot show
Abstract fetched from PubMed and read on 2026-09-19; full text not read, every identifier copied from that fetched record. The cohort is older, previously untreated adult AML - not paediatric, not KMT2A-rearranged, not B-lymphoid - so this is an import on disease, age and lineage simultaneously. The mechanistic work rests on sorted subpopulations and cell lines, and 'monocytic' is defined immunophenotypically.
Evidence that argues against this (1)
- KMT2A-rearranged disease is itself enriched for monocytic differentiation, so importing a monocytic-resistance rule into this graph risks double-counting: the property being used as a proxy for lineage is also a property of the index fusion's myeloid presentation, and in B-lymphoid infant disease it has no referent at all. Benito JM et al. 2015
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The RA1 domain of AF6 is the minimal region sufficient for MLL-AF6-mediated myeloid progenitor immortalisation and short-latency leukemogenesis in vivo, acting through self-association.
Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6. · Liedtke M, Ayton PM, Somervaille TC, Smith KS, Cleary ML · Blood 2010What this evidence cannot show
Identifier, title, journal, year and DOI fetched from PubMed on 2026-09-19 and copied from that record; abstract not re-read this cycle. Murine myeloid progenitor immortalisation and transplant models. MLL-AF6 is a KMT2A fusion but its partner is cytoplasmic and shares no mechanism with AFF1.
Evidence that argues against this (1)
- MLL-AF6 nevertheless recruits AEP constitutively despite forming no hybrid complex, so a partner with no shared domain can still converge on the same transcriptional output - which is the strongest available argument that mechanism can cross even a large partner distance. Yokoyama A et al. 2010
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
PRMT1 is an ESSENTIAL component (the paper's own word) of an MLL-EEN oncogenic transcriptional complex recruited through the adaptor Sam68, and knockdown of PRMT1 or Sam68 suppresses the transforming activity.
Protein arginine-methyltransferase-dependent oncogenesis. · Cheung N, Chan LC, Thompson A, Cleary ML, So CW · Nat Cell Biol 2007What this evidence cannot show
Identifier, title, journal, year and DOI fetched from PubMed on 2026-09-19 and copied from that record; abstract not re-read this cycle. MLL-EEN is a rare partner, not KMT2A::AFF1, and transfer of this mechanism to the infant t(4;11) disease is an assumption rather than a demonstration - which the existing gene-prmt1 entry states plainly. CORRECTED 2026-09-21 (cycle 46): the phrase 'necessary but not sufficient' is NOT the paper's. PMID 17891136's abstract says PRMT1 is an 'essential component' and contains neither the word 'necessary' nor 'sufficient'; there is no PMC record, so the full text was not read. The 'not sufficient' half was an interpolation of the same shape the coordinator committed this cycle with 'sufficient but not necessary' - completing a familiar logical pair and attaching it to a real citation. If anything the abstract cuts the other way: DIRECT FUSION of MLL with PRMT1 or Sam68 enhanced self-renewal, which is a sufficiency observation. The supported claim is 'essential component'.
Evidence that argues against this (1)
- Recruitment of an arginine methyltransferase through an adaptor is the kind of mechanism that could be partner-general, since the adaptor and not the partner supplies the contact; the rarity of MLL-EEN limits how much anyone has tested that. Mueller D et al. 2009
one of five import classes; the best-behaved
the cross-family menin dependency that argues against fusion specificity
- part of →NUP98::NSD1, t(5;11)(q35;p15.5)
a menin-dependent non-KMT2A fusion
MLL-AF6, a KMT2A fusion sharing no mechanism with AFF1