Oncofusion

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Cell statemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q-cells-saturation

Quiescence (G0) — the state 15 entries invoke to explain measurable residual disease, defined here for the first time

also called quiescence · quiescent · dormancy · G0 arrest · dormant leukaemia cell · label-retaining cell

A quiescent cell is alive but has stepped out of the cycle of growing and dividing, like a seed that stays viable in the soil without sprouting. Almost all leukaemia drugs work best on cells that are dividing, so the handful of leukaemia cells sitting in this resting state are the ones that survive treatment and can restart the disease months or years later.

The same thing, for a scientist

Quiescence is reversible exit from the cell cycle into G0, distinguished from senescence (irreversible) and from differentiation-associated arrest. In leukaemia it is the standing mechanistic explanation for minimal residual disease and late relapse. Two findings anchor it here. First, in KMT2A-rearranged AML specifically, **FOXM1 is required for LSC quiescence, survival and self-renewal**, acting by directly binding beta-catenin and stabilising it against degradation; FOXM1 inhibition suppresses leukaemogenic potential and kills primary LSCs from MLL-rearranged patients [E1]. Second, in patient-derived ALL xenografts, a rare subpopulation combining **long-term dormancy, treatment resistance and stemness** could be isolated with proliferation-sensitive dyes, and its expression profile matched primary ALL cells recovered from patients at MRD — but the adverse properties were **reversible**, with dormant cells re-entering cycle and regaining drug sensitivity once removed from the in vivo niche [E2]. Quiescence is therefore a niche-imposed, reversible state rather than a fixed cell identity, which reframes it from a property to eliminate into a property to disrupt.

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What quiescence is, in plain terms

Cells that are actively dividing run a repeating programme: grow, copy the DNA, check the copy, divide. A quiescent cell has left that loop and is sitting in a holding state called G0. It is fully alive, it makes proteins, it responds to signals — it simply is not dividing, and it can be called back into the cycle later.

This matters because of how leukaemia treatment works. Chemotherapy drugs target processes that only happen during division: copying DNA, building the spindle, separating chromosomes. A cell that is not dividing is largely invisible to most of them. The same is true of many targeted drugs whose effect depends on the cell needing to keep making new protein or new chromatin at the rate a dividing cell does.

So a treatment that clears 99.99% of a leukaemia can leave behind precisely the cells least susceptible to it, and those cells are detected as measurable (minimal) residual disease. This graph invokes that logic in fifteen places. Until now it had no entry defining what the state is.

Two things quiescence is not: it is not senescence, which is a permanent exit accompanied by a secretory programme; and it is not the differentiation block that KMT2A fusions impose, which is a failure to mature rather than a failure to divide. A blast can be differentiation-blocked and rapidly cycling at the same time — indeed most are.

The KMT2A-specific handle: FOXM1 and beta-catenin

The one published mechanism tying quiescence directly to this disease runs through FOXM1. In MLL-AF9-transformed leukaemia, Foxm1 is required in vivo for LSC survival, quiescence and self-renewal together. The mechanism is not the usual FOXM1 proliferative programme: FOXM1 upregulation activates Wnt/beta-catenin by directly binding beta-catenin and stabilising the protein against degradation, and it is that stabilisation that preserves LSC quiescence and self-renewal. FOXM1 inhibition suppresses leukaemogenic potential and induces apoptosis of primary LSCs taken from MLL-rearranged AML patients, both in vitro and in xenografts 1.

This is unusual and worth flagging: FOXM1 is normally described as a driver of proliferation across cancers, and here it is required for the opposite state. The finding therefore predicts that a FOXM1 inhibitor would act on the residual, non-dividing compartment rather than on bulk disease — which is the compartment conventional response measurements are least able to see.

Dormancy in ALL is reversible and niche-imposed

The best-characterised dormant compartment in lymphoblastic leukaemia comes from patient-derived xenografts. Using genetic engineering plus proliferation-sensitive dyes to mark cells that had not divided, a rare subpopulation was isolated with the combined properties of long-term dormancy, treatment resistance and stemness. Single-cell and bulk expression profiling showed it resembled primary ALL cells isolated from paediatric and adult patients at MRD 2.

The decisive part of that result is the last: the adverse characteristics were reversible. Once dissociated from the in vivo environment, the resistant dormant cells became sensitive to treatment and started proliferating. That makes dormancy a property of the cell-plus-niche system rather than of a hard-wired cell type, and it turns the therapeutic question from 'how do we kill a dormant cell' into 'how do we release it from the niche'.

A related but distinct state has since been described in Philadelphia-chromosome-like B-ALL: a senescence-associated stem-like dormant subpopulation regulated by AP-1 transcription factors, eradicated by dual BCL2 plus JAK/STAT or SRC/ABL inhibition, whose signature predicted poor outcomes across other high-risk childhood B-ALL subtypes 3. Whether that senescence-associated state and the reversible dormant state are the same cells under two descriptions is unresolved and is the most tractable open question here.

Why this cuts against a menin-inhibitor-only strategy

Menin inhibitors work by releasing the fusion from chromatin and allowing differentiation to resume. Differentiation is something a cell does; a cell in G0 is doing less of everything. The compartment that survives induction is, by construction, the compartment least engaged in the transcriptional programme a menin inhibitor is aimed at.

That is a prediction, not an observation — no published study has measured menin-inhibitor sensitivity as a function of cell-cycle state in KMT2A-rearranged disease, and this entry does not claim one has. It is recorded here as a falsifiable expectation, and it is the reason cell-state-cell-cycle-g1-cdk6 and this entry are linked: a CDK4/6 inhibitor pushes cells into G1 arrest, which on this reasoning would be the wrong thing to combine with a differentiating agent.

Facts and figures
ontologyGO:0044838 (cell quiescence)
state definitionReversible exit from the mitotic cell cycle into G0, retaining the capacity to re-enter cycle; distinguished from senescence (irreversible, with a secretory programme) and from differentiation-associated arrest
locationBone marrow endosteal and perivascular niches; the reversibility of the state in xenografts indicates it is niche-imposed
markers
[
  "label retention (CFSE/CellTrace dye dilution, H2B-GFP)",
  "Ki-67 negative or low",
  "2N DNA content with low RNA content (Hoechst/Pyronin Y)",
  "CDKN1B/p27 high"
]
kmt2a relevance
{
  "mechanism": "FOXM1 stabilises beta-catenin and is required for LSC quiescence, survival and self-renewal in MLL-AF9 leukaemia",
  "clinical_correlate": "the standing explanation for measurable residual disease and late relapse in KMT2A-rearranged leukaemia",
  "unresolved": "no published study measures menin-inhibitor sensitivity as a function of cell-cycle state in KMT2A-rearranged disease"
}
candidate dependencies of the state
[
  "FOXM1",
  "CTNNB1 (beta-catenin)",
  "BCL2 (in the Ph-like senescence-associated subpopulation)",
  "AP-1 family (JUN/FOS, in the Ph-like subpopulation)"
]
atlas refs
[
  {
    "label": "Dormant, therapy-resistant ALL subpopulation matching patient MRD profiles",
    "pmid": "27916615",
    "title": "Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia.",
    "authors": "Ebinger S, Özdemir EZ, Ziegenhain C, et al.",
    "venue": "Cancer Cell",
    "year": 2016,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  },
  {
    "label": "FOXM1-dependent LSC quiescence in MLL-rearranged AML",
    "pmid": "32066721",
    "title": "FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML.",
    "authors": "Sheng Y, Yu C, Liu Y, et al.",
    "venue": "Nat Commun",
    "year": 2020,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  }
]
How this could bite us back
  • A differentiating agent such as a menin inhibitor requires the cell to be transcriptionally engaged; the quiescent compartment is by construction the least engaged, so the drug class most specific to this disease may be least active against the compartment that causes relapse.
  • Combining a menin inhibitor with a CDK4/6 inhibitor would push cells into G1 arrest while asking them to differentiate, which on the reasoning above is the wrong pairing and would need to be tested before it is assumed additive.
  • Because dormancy reverses on removal from the niche, an ex vivo screen can return a clean negative for a drug that would work in vivo, and a clean positive for a drug that never reaches the dormant compartment.
  • FOXM1 is required for normal haematopoietic stem cell quiescence as well, so a FOXM1-directed therapy aimed at the leukaemic dormant compartment would be expected to disturb the normal stem-cell pool it is trying to preserve.
Still open
  1. Is menin-inhibitor sensitivity in KMT2A-rearranged leukaemia a function of cell-cycle state? Sorting blasts by Hoechst/Pyronin Y before an ex vivo sensitivity assay would answer this in one experiment and nobody appears to have done it.
  2. Are the reversible dye-dilution dormant cells of Ebinger and the AP-1-regulated senescence-associated stem-like cells of Ding the same population? The two labels are mutually exclusive as defined, and the field currently uses them interchangeably.
  3. Does the FOXM1-beta-catenin axis operate in KMT2A-rearranged ALL as it does in MLL-AF9 AML, or is it myeloid-restricted? Infant ALL is where the residual-disease problem is most acute.
  4. If dormancy is fully niche-imposed and reverses on removal from the mouse, can any ex vivo assay in current use detect a dormancy-directed drug at all?
Every source behind this entry (3)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Foxm1 is required for survival, quiescence and self-renewal of MLL-AF9-transformed leukaemia stem cells in vivo; it acts by directly binding beta-catenin and stabilising it against degradation, thereby activating Wnt/beta-catenin signalling and preserving LSC quiescence, and FOXM1 inhibition suppresses leukaemogenic potential and induces apoptosis of primary LSCs from MLL-rearranged AML patients in vitro and in xenografts.

    FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML · Sheng Y, Yu C, Liu Y, Hu C, Ma R, Lu X, et al., Qian Z · Nature Communications 2020
    PMID 32066721DOI
    What this evidence cannot show

    Principally a mouse MLL-AF9 model with primary patient LSC validation; FOXM1 inhibition used a peptide/small-molecule approach rather than a clinical-grade agent, and 'quiescence' is scored by cell-cycle distribution rather than by label retention. The result runs against FOXM1's usual pro-proliferative characterisation, which means either the mechanism is context-specific or the readout is measuring something adjacent to G0. Read: abstract only.

    Evidence that argues against this (1)
    • The founding description of the MLL-AF9 leukaemia stem cell points the other way on cell-cycle state: LSCs isolated from leukaemias initiated in committed granulocyte-macrophage progenitors retained the immunophenotype and global expression profile of normal GMP, a proliferative progenitor compartment, while re-activating only a limited stem-cell self-renewal programme. If the MLL-AF9 LSC is fundamentally a cycling progenitor with a self-renewal module bolted on, then quiescence is a minority state within the LSC compartment rather than its defining property, and a FOXM1-dependent quiescent fraction may be a small subset. Read: abstract only. Krivtsov AV et al. 2006
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In patient-derived xenografts of acute lymphoblastic leukaemia, a rare subpopulation identified with proliferation-sensitive dyes combined long-term dormancy, treatment resistance and stemness, and resembled primary ALL cells isolated from paediatric and adult patients at minimal residual disease; these adverse characteristics were reversible, with resistant dormant cells becoming treatment-sensitive and re-entering proliferation once dissociated from the in vivo environment.

    Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia · Ebinger S, Ozdemir EZ, Ziegenhain C, Tiedt S, Castro Alves C, Grunert M, et al., Jeremias I · Cancer Cell 2016
    PMID 27916615DOI
    What this evidence cannot show

    Patient-derived xenografts in immunodeficient mice, so the niche imposing dormancy is a murine one; the panel of PDX models is small and not selected for KMT2A rearrangement, so the extent to which infant KMT2A-rearranged ALL carries this compartment is not established by this study. Dye-dilution marks cells that have not divided, which is a necessary but not sufficient criterion for G0. Read: abstract only.

    Evidence that argues against this (1)
    • Reversibility undercuts the therapeutic framing as much as it supports the biology. If dormancy is entirely niche-imposed and lost on removal from the mouse, then every ex vivo drug-sensitivity measurement in this disease, including the ones this graph relies on for menin-inhibitor sensitivity, is made on cells that have already exited the state that mattered. A dormancy-directed therapy could not be screened by the assays currently in use, and an ex vivo negative result would not exclude in vivo activity. The paper's own conclusion — that patients might benefit from strategies that release MRD cells from the niche — concedes that the state cannot be attacked directly. Read: abstract only (same paper). Ebinger S et al. 2016
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Single-cell multiomic profiling of residual cells from CRLF2-rearranged and ABL1-rearranged Ph-like ALL patient-derived xenografts treated in vivo with targeted inhibitors defined a dormant leukaemia subpopulation with senescence-associated stem-cell-like features regulated by AP-1 transcription factors; it was eradicated by dual pharmacological inhibition of BCL-2 with JAK/STAT or SRC/ABL, and its single-cell-derived signature predicted poor clinical outcomes in other high-risk genetic subtypes of childhood B-ALL.

    Targeting senescent stemlike subpopulations in Philadelphia chromosome-like acute lymphoblastic leukemia · Ding YY, Sussman JH, Madden K, Loftus JP, Chen RK, Falkenstein CD, et al., Tasian SK · Blood 2025
    PMID 39774844DOI
    What this evidence cannot show

    Ph-like ALL, not KMT2A-rearranged disease; the extension to other high-risk subtypes is a signature-scoring association, not a demonstration that the same cells exist in KMT2A-rearranged leukaemia. 'Senescence-associated' and 'dormant' are used together here, which conflicts with the standard distinction between reversible quiescence and irreversible senescence. Read: abstract only.

    Evidence that argues against this (1)
    • The two dormant states described in ALL may not be the same thing and the literature does not yet reconcile them. The PDX dormant compartment isolated by dye dilution was explicitly REVERSIBLE — cells resumed cycling and regained drug sensitivity on removal from the niche — whereas a senescence-associated programme is by definition not reversible. Either the AP-1-regulated population is quiescent rather than senescent and the label is loose, or the two studies describe different cells, in which case a signature built from one will not identify the other. Read: abstract only. Ebinger S et al. 2016
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