Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here
also called adult HSC · BM HSC · CD34+CD38-CD90+CD45RA- HSC · long-term HSC
After birth, blood stem cells live in the bone marrow. Putting the KMT2A::AFF1 fusion into these postnatal stem cells is much harder to turn into leukaemia than putting it into fetal cells, which is a central clue about why infant disease is different.
The same thing, for a scientist
The postnatal bone marrow haematopoietic stem cell (human: Lineage-negative CD34-positive CD38-negative CD45RA-negative CD90-positive; CL:0001024) is the standard reference compartment against which fetal origin claims are tested. It matters to this project in three ways: it is the compartment in which enforced MLL-AF4 expression conspicuously fails to initiate leukaemia, it is the compartment whose menin dependency sets the therapeutic index of menin inhibition, and it is the anatomical and functional context in which KMT2A-rearranged AML and therapy-related KMT2A-rearranged leukaemia arise in older patients.
The failure that is informative
Enforced MLL-AF4 expression in human cord blood CD34-positive HSPCs increased clonogenicity, proliferation, survival and multilineage repopulating capacity, and improved homing after intra-bone-marrow transplantation, yet did not initiate leukaemia 1. Adding activated KRAS enhanced extramedullary engraftment and migration and still did not initiate leukaemia 2.
A negative result in a xenograft is weak evidence on its own. What makes this pair informative is the contrast with the positive result obtained when an authentic t(4;11) was engineered into primary human fetal liver cells, where the clinical phenotype and a fetal-specific program both appeared 3. Same fusion, different cellular substrate, different outcome. The postnatal stem cell is not a neutral background; it is a restrictive one.
Cord blood is, strictly, neonatal rather than adult, which if anything strengthens the argument: even the youngest available postnatal stem cell already lacks whatever the fetal liver supplies.
Committed progenitors can be the origin — for the myeloid fusions
It would be wrong to conclude that only stem cells can be cells of origin for KMT2A fusions. The foundational experiment in this field showed the opposite for the myeloid side. Leukaemia stem cells isolated from leukaemias initiated by MLL-AF9 in committed granulocyte-macrophage progenitors transferred disease with as few as four cells, and retained an immunophenotype and global expression profile very similar to normal GMPs, while re-activating a limited subset of genes highly expressed in normal haematopoietic stem cells 4.
That result reframes 'cell of origin' as a question about which self-renewal program gets switched on in which differentiation state, not about which gate the cell was sorted from. A KMT2A fusion does not need to start in a stem cell; it needs to install a stem-cell-like self-renewal module into whatever cell it lands in. The cell-state-stem-like-self-renewal node develops this.
Why this compartment sets the therapeutic index
Every menin-directed therapy is dosed into a patient whose normal blood depends on this compartment. The relevant finding is that conditional menin deletion in mouse haematopoiesis leaves steady-state progenitor numbers largely intact but reveals a marked functional defect in long-term haematopoietic stem cells under competitive transplantation 5. Steady-state normality plus stress-exposed fragility is the worst combination for a relapsed infant: haematopoietic recovery after intensive therapy is exactly a stress condition, and any impairment will be clinically indistinguishable from persistent disease.
The same compartment is where KMT2A-rearranged AML and therapy-related KMT2A-rearranged leukaemia arise in older patients after topoisomerase-II-poison exposure, so the bone marrow HSC is simultaneously the target of the toxicity and the origin of a different KMT2A disease.
| ontology | CL:0001024 |
|---|---|
| location | Postnatal bone marrow; endosteal and perivascular niches |
| developmental stage | postnatal / adult |
| role in project | negative control for fetal origin; the compartment whose menin dependency sets the therapeutic index; origin compartment for KMT2A-rearranged AML and therapy-related KMT2A leukaemia |
ontology alternatives
[ "CL:0000037" ]
markers
[ "Lineage-", "CD34+", "CD38-", "CD45RA-", "CD90/THY1+", "CD49f+" ]
atlas refs
[
{
"label": "MLL-AF4 in human cord blood CD34+ HSPC, xenograft",
"pmid": "21389315",
"title": "Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia.",
"authors": "Montes R, Ayllón V, Gutierrez-Aranda I, et al.",
"venue": "Blood",
"year": 2011,
"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": "MLL-AF9 GMP-initiated leukaemia stem cell, 4-cell transfer",
"pmid": "16862118",
"title": "Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.",
"authors": "Krivtsov AV, Twomey D, Feng Z, et al.",
"venue": "Nature",
"year": 2006,
"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."
}
]- Menin is required for long-term HSC function under competitive stress, so menin inhibition may impair haematopoietic recovery in exactly the post-induction window where it is hardest to attribute.
- If KMT2A fusions can install self-renewal into a committed progenitor, then depleting a stem-cell-like population is not sufficient: the disease can be re-seeded from a differentiated compartment.
- The bone marrow HSC is both the site of therapy-related KMT2A leukaemia and the compartment we must preserve, so any DNA-damaging or chromatin-perturbing intervention carries a second-cancer risk in the same cells.
- Is the postnatal restriction on MLL-AF4 transformation quantitative (needs more hits) or qualitative (needs a program that no longer exists)? A matched CRISPR t(4;11) in adult bone marrow CD34+ cells versus fetal liver cells would settle it and has apparently not been published.
- Does menin inhibition impair human long-term HSC function under the specific stress of post-chemotherapy recovery, and can that be distinguished prospectively from persistent leukaemia?
- Do KMT2A-rearranged AML and therapy-related KMT2A leukaemia in adults share the fetal program, or have they found a different permissive state?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Enforced MLL-AF4 expression in human cord blood CD34-positive HSPCs enhances repopulating and clonogenic function, proliferation and survival and improves homing, but is not sufficient to initiate leukaemia.
Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia · Montes R, Ayllon V, Gutierrez-Aranda I, Prat I, Hernandez-Lamas MC, Ponce L, Bresolin S, te Kronnie G, Greaves M, Bueno C, Menendez P · Blood 2011What this evidence cannot show
Cord blood is neonatal rather than adult bone marrow. Enforced lentiviral expression lacks the native promoter, correct stoichiometry and the reciprocal AF4-MLL product. Xenograft negatives depend on recipient strain and follow-up length.
Evidence that argues against this (1)
- A high-titre retroviral MLL-Af4 in human CD34+ cells did generate a faithful t(4;11) pro-B ALL model, so postnatal CD34+ cells are not absolutely refractory. Lin S et al. 2016
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Activated KRAS cooperates with MLL-AF4 to promote extramedullary engraftment and migration of human cord blood CD34-positive HSPCs but is insufficient to initiate leukaemia.
Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia · Prieto C, Stam RW, Agraz-Doblas A, Ballerini P, Camos M, Castano J, Marschalek R, Bursen A, Varela I, Bueno C, Menendez P · Cancer Research 2016What this evidence cannot show
Enforced expression of both lesions; RAS pathway mutations in patients are frequently subclonal and lost at relapse, so their role may be in progression rather than initiation.
Evidence that argues against this (1)
- Insufficient to initiate leukaemia is the load-bearing half of this result and it is in neonatal cord blood. The comparison that matters is with the fetal-liver CRISPR model in this same entry, which does produce infant-ALL programmes. Oncofusion knowledge graph (internal analysis) 2026
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
An authentic CRISPR-engineered t(4;11) in primary human fetal liver haematopoietic cells does replicate the clinical features of infant ALL and drives fetal-specific and infant-ALL-specific programs, in contrast with the postnatal CD34-positive results.
A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program · Rice S, Jackson T, Crump NT, Fordham N, Elliott N, O'Byrne S, Lara Fanego MDM, Addy D, Crabb T, Dryden C, Inglott S, Ladon D, Wright G, Bartram J, Ancliff P, Mead AJ, Halsey C, Roberts I, Milne TA, Roy A · Nature Communications 2021What this evidence cannot show
The fetal and postnatal experiments were not run side by side with matched gene delivery methods, so part of the contrast may be technical (CRISPR-engineered endogenous translocation versus lentiviral overexpression) rather than developmental.
Evidence that argues against this (1)
- An authentic engineered translocation in fetal liver cells is the strongest model in this beat and it inherits the limits of the system: primary human cells in culture or xenograft, a single or small number of donors, and a readout of transcriptional programmes rather than of a transplantable leukaemia in an immunocompetent host. Driving infant-ALL-specific programmes is not the same as producing the disease. Oncofusion knowledge graph (internal analysis) 2026
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Leukaemia stem cells from MLL-AF9 leukaemias initiated in committed granulocyte-macrophage progenitors transfer leukaemia with as few as four cells while retaining a GMP-like immunophenotype and global expression profile, with re-activation of a limited subset of normal haematopoietic-stem-cell genes.
Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9 · Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA · Nature 2006What this evidence cannot show
Mouse retroviral MLL-AF9 model of myeloid leukaemia; the lymphoid t(4;11) disease may not obey the same rules, and 2006-era expression profiling cannot resolve the intra-population heterogeneity that single-cell methods now show.
Evidence that argues against this (1)
- Murine retroviral MLL-AF9 in the myeloid compartment, and the index disease is human infant KMT2A::AFF1 B-lymphoid leukaemia. Transfer from four cells is measured in syngeneic recipients under conditions that maximise engraftment, and re-activation of HSC-restricted genes in a GMP-like cell is what forced expression of a self-renewal oncogene produces rather than evidence about the physiological cell of origin. Oncofusion knowledge graph (internal analysis) 2026
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Conditional menin loss in mouse haematopoiesis preserves steady-state multilineage and myelo-erythroid progenitor numbers but reveals a marked long-term haematopoietic stem cell defect on competitive transplantation.
Menin regulates the function of hematopoietic stem cells and lymphoid progenitors · Maillard I, Chen YX, Friedman A, Yang Y, Tubbs AT, Shestova O, Pear WS, Hua X · Blood 2009What this evidence cannot show
Complete conditional gene deletion in mouse is a harsher perturbation than reversible partial pharmacological occupancy, and competitive transplantation is a severe stress test that may overstate the clinical effect.
Evidence that argues against this (1)
- This is the safety-relevant result of the beat and it is a mouse. Preserved steady-state progenitors with a long-term HSC defect revealed only under competitive transplantation describes a reserve that ordinary haematopoiesis does not draw on — but patients on menin inhibitors do face marrow stress, and the human equivalent of competitive transplantation has not been measured. Journal of Clinical Oncology 2025
- E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Cell Ontology provides CL:0001024 for the CD34-positive CD38-negative haematopoietic stem cell and CL:0000037 for the haematopoietic stem cell generally.
Cell Ontology term lookup via the EMBL-EBI Ontology Lookup Service OLS4 API · EMBL-EBI Ontology Lookup Service; Cell Ontology consortium · Database 2026What this evidence cannot show
Ontology marker definitions are partly mouse-derived and are not a substitute for a validated clinical flow panel.
Evidence that argues against this (1)
- Cell Ontology identifiers give the entry a resolvable name for the compartment and no information about it. CL:0001024 is defined by two surface markers, which is coarser than the functional HSC the rest of the entry discusses. OBO Foundry / EMBL-EBI OLS 2026
HSC-derived niche cell regulating the stem-cell pool
the adult counterpart from which the fetal signature was derived by contrast
postnatal counterpart; restrictive rather than permissive for MLL-AF4 transformation
conditional menin loss preserves steady-state progenitors but causes a marked long-term HSC defect under competitive transplantation
the normal compartment whose menin dependency sets the therapeutic index
- ← related toWhere KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
the marrow niche the leukaemia occupies and displaces
LEDGF/p75 is DISPENSABLE here - conditional loss leaves murine haematopoiesis essentially intact
- depends on →MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is
MLLT3 governs human HSC self-renewal and engraftment - a wild-type, normal-cell requirement
adult HSCs are intrinsically PROTECTED against MLL-ENL transformation, which closes the window at the late end
MOF acetyltransferase activity is required for ADULT murine haematopoiesis
the PAF1c subunit CDC73 is required for murine HSC maintenance while regulating leukaemia-specific genes
- depends on →DPY30 — the smallest COMPASS subunit, and the only one that behaves like a selective dependency
Dpy30 is critical for maintaining the identity and function of ADULT murine haematopoietic stem cells
- ← related toMechanism class 5 — enhancer hijacking (inv(3) GATA2/EVI1 — and DUX4-r, which only half belongs here)
Two cooperating arms plus a pre-leukaemic interval (Yamaoka 2020, PMID 32330245): inv(3)-driven EVI1 skews megakaryocyte/myeloid progenitors, Gata2 haploinsufficiency enhances it, and only together do they give leukaemia - after a serially-replating pre-leukaemic population appears.
On-target host cost (Growney 2005, PMID 15784726): adult conditional Runx1 deletion blocks common lymphoid progenitor production, impairs platelet output and produces a myeloproliferative phenotype - systemic RUNX1 inhibition installs a pre-malignant expansion in normal marrow.
Non-redundant in the tumour is also non-redundant in the host (Growney 2005, PMID 15784726): adult Runx1 loss blocks CLP production, impairs platelets and drives myeloproliferation.
Hira deletion rapidly depletes adult mouse HSCs and de-represses erythroid genes - contested
- ← regulatesHistone H3.3 - one protein, two genes, and the reason this graph should not file it as gene-h3f3a
H3.3-null HSPCs exhaust prematurely; H3K27me3 gain, H3K9me3 loss at ERVs
- ← regulatesNormal blood needs DOT1L too - lose it in an adult mouse and the marrow fails within weeks
long-term HSCs depleted after acute Dot1l loss
the normal-marrow HOXA9 body pattern was measured in primary human bone-marrow cells
maintains HSC self-renewal, retention and quiescence
CXCL12-CXCR4 retention and quiescence; SCF survival
adipocyte-rich marrow has fewer HSCs; fatless mice engraft faster after irradiation
forcing quiescent HSCs into cycle depletes the long-term repopulating pool
Hard limitation verified 2026-09-19: GTEx has 54 tissues, none of them bone marrow, and 980 donors none under age 20 - so it cannot provide the paediatric marrow baseline a toxicity filter needs.
adult-derived progenitor arm of the crossed design
KDM3 inhibition raises KMT2A copy gains in primary cord-blood CD34+ HSPCs and in primary AML cells and organoids
KMT2A copy gain and break-apart in primary cord-blood CD34+ HSPCs at 1 uM for 72 h - the cells its discovery paper reports as spared
cord-blood CD34+ HSPCs are the obtainable proxy; the index disease starts in a fetal progenitor
CD34-positive bone-marrow haematopoietic progenitors, two donors, resting
the CD34+ arm targets this compartment
SATB1 level partitions HSCs into interconvertible lymphoid-biased (SATB1-high) and myeloid-biased (SATB1-low) populations
modest steady-state phenotype but ARID1B-dependent myeloid reconstitution on transplantation; ARID1A/ARID1B double loss causes acute bone-marrow failure
transforming target in the founding model is primary murine bone-marrow haematopoietic stem/progenitor cells (MOUSE); the human disease is a CD34+/CD117+ minimally differentiated blast
MOUSE: high in fetal HSCs and required to sustain them; conditional knockout in adults EXPANDS HSCs and progenitors and makes them cycle hyperactively
two genome-wide H4K20me1 profiles exist in PRIMARY HUMAN haematopoietic stem/progenitor cells; neither is retrievable from a leukaemia-scoped query, which is why this graph recorded the mark as unmeasured in blood
the compartment in which the Mll-dependent quiescence set-point was measured
HSC: required, quiescence maintained
the compartment the defect is measured in
the reference population the signature is named after; resemblance is transcriptional and epigenetic, not functional
the calibration sample is primary CD34+ HSPC
CD34+ HSPCs as the fusion-negative control
TCF3-ZNF384 detectable in a subset of HSCs and in multiple myeloid- and lymphoid-potent progenitors, unlike Ph-like B-ALL
CXCR4 signalling maintains the adult HSC pool
Evi-1 expression in MLL-AF9 leukaemia stem cells is inherited from an HSC cell of origin, not from a GMP
Erg is required for HSC self-renewal under transplantation and myelotoxic stress, not at steady state
normal expression restricted to HSC, progenitors and early erythroid/megakaryocytic cells; essential for HSC generation and survival
ziftomenib plus selinexor suppressed colony formation of primary CD34-positive KMT2A-rearranged progenitors WITHOUT affecting normal stem cells - a sparing claim, not a requirement claim, from a preprint
- ← related toPPIE (CyP33) — the off-switch the fusion throws away, and the reason PHD3 reinsertion kills transformation
re-inserting the CyP33-binding KMT2A PHD3 into MLL-ENL BLOCKS haematopoietic stem cell immortalisation; the cell type in which PPIE's absence is necessary for transformation, not one in which PPIE is required
- ← regulatesCSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology
Vav-iCre Csnk2a1 deletion expands the HSC and early progenitor compartments without killing them; maintains-a-state, mouse, no fusion context
KDM4 activity is required for HSC maintenance in vivo - but only shown in a Kdm4a/b/c TRIPLE knockout, so this is family-level and not attributable to KDM4C; a toxicity result for continuous KDM4 inhibition
- ← depends onUBE2T — E2; rank 33 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
biallelic UBE2T loss causes Fanconi anaemia with progressive bone marrow failure, and somatic reversion of a UBE2T allele IN PATIENT HSCs prevented marrow failure; human germline genetics, no KMT2A-rearranged arm anywhere (0 records)
METTL3 mRNA and protein are higher in AML cells than in healthy HSPCs, and depleting it in normal HSPCs promotes differentiation - expression AND requirement in the normal compartment, which is the toxicity argument
Bcor inactivation in murine HSCs expands myeloid progenitors and cooperates with KrasG12D to initiate transplantable acute leukaemia, with Hoxa7/Hoxa9 among the derepressed PRC1 targets
the haematopoietic cell type in which UTX loss has a measured phenotype is the HSPC, where differentiation is blocked and H3K4 methylation falls through the COMPASS-like complex
the one KMT2A-context cell-type result for EZH1 is in iPSC-derived haematopoietic stem and progenitor cells from a KMT2A::MLLT3 AML patient, and it is a dual EZH1/2 plus hypomethylating-agent result rather than an EZH1-resolved one
- ← related toMLLT6 (AF17) — the fourth KMT2A fusion partner inside DotCom, and the only one no cell needs
EXPLICIT NEGATIVE: Af17-null mice show no gross haematopoietic abnormality at steady state, with no transplant, stress challenge or fusion cross performed (murine germline knockout; PMID 21170927)
conditional Kat5/Tip60 knockout shows a critical, HAT-activity-dependent requirement for adult haematopoietic stem cell maintenance (murine; PMID 32542325)
- ← depends onFANCL — FA core complex; rank 26 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
FANCL knock-down in primary HUMAN CD34+ cells reduces beta-catenin-active cells and inhibits multilineage progenitor expansion (PMID 22653977)
de-repressed p16Ink4a and p19Arf cause premature loss of self-renewing HSCs in Bmi1-deficient mice; deleting both frames restores self-renewal (PMID 16954369)
- ← regulatesFANCD2 — the FA effector menin binds, and the weakest FA gene in this graph's own selectivity scan
REQUIRED IN: in Fanconi anaemia patients the FA pathway is required in haematopoietic stem and progenitor cells, which are depleted before clinical marrow failure - pathway-level, no fusion present (PMID 22683204)
- ← regulatesFANCI — ID2 module; rank 15 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
REQUIRED IN: FA-pathway requirement in haematopoietic stem and progenitor cells, measured in Fanconi anaemia patients with no fusion (PMID 22683204)
REQUIRED IN: FA-pathway requirement in haematopoietic stem and progenitor cells, measured in Fanconi anaemia patients with no fusion (PMID 22683204)
REQUIRED IN: FA-pathway requirement in haematopoietic stem and progenitor cells, measured in Fanconi anaemia patients with no fusion; biallelic BRIP1 loss defines FA-J (PMID 22683204)
NEGATIVE/CONTEXT edge: no haematopoietic cell type has been measured for BOD1L; the HSPC requirement documented for this pathway comes from fusion-free Fanconi anaemia patients, not from BOD1L (PMID 22683204)
REQUIRED IN: SIRT1 is required for homeostatic haematopoietic stem cell maintenance via FOXO3, and its deletion gives an aging-like HSC phenotype - murine normal haematopoiesis, no fusion present (PMID 25068121)
ORIGIN-OF-MODEL edge, not a normal-HSC requirement: the human MLLr model in which MAT2A inhibition kills and synergises with JQ-1 is built by CRISPR rearrangement of normal human CD34+ cells (PMID 37148657)
the compartment in which failure of this state's repair arm is most costly: FA patients lose HSPCs through a p53/p21 arrest before clinical marrow failure
- ← expressed inKDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit
murine HSC transgenic over-expression gives fully penetrant myeloid or B-lymphoid leukaemia; CxxC-domain deletion in haematopoietic cells gives T-ALL
murine titratable transgenic: intermediate HOXA10 gives a 15-fold HSC repopulating increase, high HOXA10 gives none
p53 maintains murine HSC quiescence at steady state through Gfi-1 and Necdin - a non-damage role
ATR deletion in adult mice causes acute loss of tissue stem and progenitor cells with thymic involution and premature-ageing phenotypes
murine Rad21 haploinsufficiency reduces competitive reconstitution specifically in the lymphoid compartment, leaving myeloid chimerism unaffected
- ← expressed inSTAG2 - the cohesin subunit that defines secondary AML, and the one whose loss a KMT2A fusion does not care about
murine Stag2 deletion in HSPCs increases self-renewal and impairs differentiation; concurrent Stag1 loss abrogates haematopoiesis
HDAC5 is a negative regulator of human cord-blood HSC homing: inhibiting it raises CXCR4 and improves long-term and secondary engraftment
- ← expressed inFANCG — FA core complex; rank 27 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
FA pathway loss depletes human HSPCs before clinical marrow failure, through hyperactivated p53 and a late p21-dependent G0/G1 arrest that p53 knockdown rescues
- ← expressed inFAAP100 — FA core complex; rank 36 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
FAAP100 loss causes Fanconi anaemia in patients, and the FA HSPC defect precedes clinical marrow failure and is p53/p21-driven and p53-knockdown-reversible
oestrogen acting through ERalpha raises HSC self-renewal in female mice and in pregnancy (PMID 24451543); HPA records ESR1 undetected in mature immune cells
- ← expressed inNLRC5 - the MHC class I transactivator, and the route by which interferon activates class I when KMT2A and KMT2B are both gone
HPA RNA tissue-enhanced in bone marrow (33.8 nTPM) and lymphoid tissue (31.8 nTPM), its two highest tissues
essential m6A target for HSC self-renewal and quiescence (mouse, with human engraftment arm)
preferentially expressed in mouse and human HSC-enriched populations; required for LT-HSC activity
- ← expressed inCDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion
CDC73 is cell-autonomously required for adult haematopoietic stem cell function in vivo and for fetal haematopoiesis; loss in haematopoietic cells is lethal through bone marrow failure, with cell-cycle defects in progenitors (PMID 31031188, mouse conditional knockout). A requirement, not an image (Q95 2026-09-22)
mouse conditional Elp3 inactivation kills committing progenitors and compromises HSC grafting - the only haematopoietic experiment in the Elongator literature
restrains mature lineage programs from being expressed too early in HSPCs; Zeb1/Zeb2 loss causes acute marrow failure