Quiescence in the blood stem cell is actively held there by MLL1 - and losing MLL1 pushes the stem cell INTO cycle while pulling the progenitor OUT of it
also called Mll-dependent HSC quiescence · G0 maintenance by MLL1
Blood stem cells spend most of their life asleep, and the gene that breaks in infant leukaemia is one of the things keeping them asleep. Take it away and the stem cells wake up and burn out, but the slightly more mature cells one step down do the opposite and slow down.
The same thing, for a scientist
In an inducible Mll knockout, HSCs lacking Mll show ectopic cell-cycle entry and the quiescent HSC pool is depleted, while Mll deletion in myelo-erythroid progenitors gives REDUCED proliferation and a reduced response to cytokine-driven cell-cycle entry [E1]. An independently derived conditional allele reports the same directional result in the fetal compartment: Mll-null embryos surviving to E16.5 have reduced HSC numbers and a greatly reduced quiescent fraction, and those HSCs cannot compete in transplantation [E2]. So MLL1 is not a generic proliferation factor. It sets OPPOSITE cell-cycle set-points in two adjacent compartments, and the direction flips exactly at the stem-cell/progenitor boundary. This matters to the index fusion for a reason nobody has tested: the fusion retains the MLL1 N-terminus and loses the SET domain, and the wild-type allele's quiescence function has never been measured in a cell that also carries a KMT2A fusion.
The direction reverses one step down the hierarchy
Jude et al. deleted Mll with an inducible allele in adult mice. The HSC phenotype is ectopic cell-cycle entry and depletion of the quiescent HSC pool; the myelo-erythroid progenitor phenotype, in the same animals, is reduced proliferation and a blunted response to cytokine-induced cell-cycle entry 1.
Read as a cell state rather than as a knockout phenotype, that says MLL1 is doing two different jobs: maintaining quiescence in HSCs and promoting proliferation in progenitors - the authors' own summary sentence. A single 'MLL1 supports self-renewal' statement flattens this, and the flattened version is the one that normally reaches reviews.
The fetal arm agrees about quiescence and disagrees about severity
McMahon et al., published in the same issue of Cell Stem Cell from a different conditional allele, found Mll-null embryos surviving to E16.5 with reduced HSC numbers, a greatly reduced quiescent fraction, and failure to compete in transplantation 2.
On quiescence the two papers agree. On steady-state adult haematopoiesis they do not - see concept-two-founding-mll-conditional-knockouts-disagree-about-steady-state-blood. The quiescence result is therefore the part of this story that is replicated across two labs and two alleles, and it is the part this graph should lean on.
What is NOT established, and why it is the interesting gap
Every measurement above is murine and wild-type. No experiment has asked whether the quiescence set-point of a normal HSC is altered by the presence of a KMT2A fusion, and no experiment has asked whether a menin inhibitor - which evicts menin from MLL1 targets - moves the HSC quiescence set-point.
The second question is directly clinically live, because the documented normal-tissue liability of menin inhibition is impaired HSC function under stress rather than steady-state myelosuppression (gene-men1 E3), and a stress response is a cell-cycle re-entry phenotype.
| state class | cell-cycle set-point |
|---|---|
| system | mouse, conditional and constitutive Mll alleles; no human measurement |
| shown for fusion | NO - nobody has looked in any KMT2A fusion. Every measurement here deletes the whole Mll locus in a fusion-free animal, so it says nothing about the wild-type allele's quiescence function in a cell that also carries a fusion. |
| relation to existing entries | DISTINCT from cell-state-quiescence, which is about LSC and MRD dormancy in established leukaemia (FOXM1-beta-catenin, reversible niche-imposed dormancy in PDX). This entry is about the NORMAL stem cell's cell-cycle set-point and the gene that breaks. They should be read together, not merged. |
compartments
{
"HSC": "quiescence MAINTAINED by Mll; loss causes ectopic cell-cycle entry and depletion of the quiescent pool [E1]; fetal Mll-null HSC quiescent fraction greatly reduced [E2]",
"myelo_erythroid_progenitor": "proliferation PROMOTED by Mll; loss causes reduced proliferation and blunted cytokine-driven cell-cycle entry [E1]",
"committed_lymphoid_and_myeloid": "no longer Mll-dependent [E1]"
}- If MLL1 holds HSC quiescence and a menin inhibitor partially disables MLL1 target-gene expression, the drug could push normal HSCs into cycle - a toxicity invisible in a steady-state blood count that only shows after a second stress such as transplant conditioning.
- The opposite sign in progenitors means a single readout pooled across compartments can report 'no effect' by averaging an increase against a decrease. Any normal-haematopoiesis safety study of a menin inhibitor must be compartment-resolved or it is uninterpretable.
- Does a menin inhibitor move the HSC quiescence set-point? Revumenib's documented normal-blood liability is impaired recovery under stress rather than steady-state myelosuppression, and stress recovery is cell-cycle re-entry, so a Ki-67/Hoechst or label-retention readout on LSK cells after 14 days of a menin inhibitor is the direct experiment and has not been reported.
- Is the wild-type MLL1 allele still holding quiescence in a KMT2A-rearranged cell? The fusion acts as a dominant negative for ATR-mediated stabilisation of wild-type MLL (see cell-state-unsynchronisable-cell-cycle), so the wild-type allele's quiescence function may already be compromised in the leukaemic cell before any drug is given.
- Which side of the Artinger menin-dependent versus menin-independent split does the quiescence programme fall on? If quiescence is menin-INDEPENDENT, a menin inhibitor should leave it intact, and that is a cheap, scoreable prediction.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In an inducible adult Mll knockout, HSCs lacking Mll exhibit ectopic cell-cycle entry resulting in depletion of quiescent HSCs, while Mll deletion in myelo-erythroid progenitors results in reduced proliferation and a reduced response to cytokine-induced cell-cycle entry; committed lymphoid and myeloid cells no longer require Mll.
Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. · Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P · Cell Stem Cell 2007What this evidence cannot show
Mouse, inducible conditional knockout of the whole Mll locus, so this is a statement about wild-type MLL1 and not about a fusion allele. ABSTRACT READ ONLY: the PMC full-text route returned an empty body for PMC2234224 on 2026-09-23, so the cell-cycle percentages, the quiescence assay used and the n are not quoted here and must be pulled from the paper before any number is stated. Separately, the PubMed MCP tool's abstract for this record has every italicised 'Mll' deleted (it renders as 'thatis essential'), which is this project's documented italic-symbol deletion trap; the gene symbol in this claim was restored by hand from the title and the PubMed web record.
Evidence that argues against this (1)
- The same journal issue carries a second conditional Mll allele reporting GROSSLY NORMAL steady-state haematopoiesis in bone marrow, thymus and spleen, against this paper's fatal bone marrow failure within 3 weeks of deletion. The quiescence direction agrees; the severity does not. McMahon KA et al. 2007
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Mll-null embryos survive to E16.5 with reduced HSC numbers; the quiescent fraction of those HSCs is greatly reduced and they cannot compete with wild-type cells in transplantation, and conditionally Mll-deleted adult bone marrow is highly compromised in competitive reconstitution despite grossly normal steady-state haematopoiesis.
Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. · McMahon KA, Hiew SY, Hadjur S, Veiga-Fernandes H, Menzel U, Price AJ, Kioussis D, Williams O, Brady HJM · Cell Stem Cell 2007What this evidence cannot show
Mouse; abstract read, full text not opened. 'Greatly reduced' is the authors' own wording and no percentage is quoted here because none appears in the abstract. The fetal result is a constitutive-null embryo and the adult result a conditional deletion, so the two halves of this paper are not the same experiment and should not be pooled.
Evidence that argues against this (1)
- This paper's adult arm reports grossly normal steady-state haematopoiesis, while the paper published immediately before it in the same issue reports fatal bone marrow failure within three weeks of deletion. The quiescence direction survives the disagreement; the severity of the requirement does not, and a reader should not take either paper's whole-animal phenotype on its own. Jude CD et al. 2007
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The Mll-dependent transcriptional network in haematopoietic stem cells extends well beyond the clustered Hox genes, contains many characterised regulators of self-renewal, and splits into target genes that are dependent on and independent of the MLL cofactor menin; PRDM16 emerged as the single target uniquely effective at partially rescuing Mll-deficient haematopoietic stem and progenitor cells.
An MLL-dependent network sustains hematopoiesis. · Artinger EL, Mishra BP, Zaffuto KM, Li BE, Chung EKY, Moore AW, Chen Y, Cheng C, Ernst P · Proc Natl Acad Sci U S A 2013What this evidence cannot show
Mouse; abstract read, full text not opened. The menin-dependent versus menin-independent split is the load-bearing part for this graph, and the abstract states it without naming which genes fall on which side, so that partition must not be quoted gene-by-gene from here. This PMID was already cited once in the corpus (collab-ernst-colorado) and its conclusion had never been written into gene-kmt2a.
Evidence that argues against this (1)
- If the Mll-dependent network is largely menin-INDEPENDENT, the quiescence programme may be untouched by a menin inhibitor, which would make this entry's clinical open question moot. The abstract does not resolve which targets fall on which side, so the entry's clinical framing rests on an unresolved partition. Mishra BP et al. 2014
- ← regulatesKMT2A / MLL1 — the gene that breaks
MLL1 maintains HSC quiescence; loss causes ectopic cell-cycle entry (PMID 18371366)
the compartment in which the Mll-dependent quiescence set-point was measured
the normal-stem-cell counterpart of the leukaemic dormancy entry; deliberately NOT merged
the fusion's cell-cycle phenotype, against which this wild-type set-point is the comparator
fetal arm: Mll-null E16.5 HSCs have a greatly reduced quiescent fraction (PMID 18371367)
the replicated half of the pair is the quiescence result
- ← analogous toThe endocrine cell's resting state is an actively maintained G1 restraint, and menin is what maintains it
the same architecture in blood - an actively maintained resting state under MLL1 control - with the opposite consequence on release