Megakaryocyte-erythroid progenitor (MEP) — the branch KMT2A fusions almost never take, which is why it was a usable control
also called MEP · megakaryocyte-erythroid progenitor · megakaryocyte/erythrocyte progenitor · Lin-CD34+CD38+IL-3Ra-CD45RA-
The megakaryocyte-erythroid progenitor is the bone-marrow cell that makes red blood cells and the giant cells that shed platelets. KMT2A-rearranged leukaemia essentially never comes from this branch, and that absence turned out to be useful: it let the project rule out one explanation for its iron-and-haem finding.
The same thing, for a scientist
The MEP (CL:0000050) is the bipotent myeloid progenitor that gives rise to erythrocytes and megakaryocytes, prospectively isolable in human marrow and cord blood as Lin-CD34+CD38+ IL-3R-alpha-negative CD45RA-negative, the sibling of the GMP downstream of the common myeloid progenitor [E1]. It earns an entry in this graph for a negative reason that turned out to be load-bearing. Because erythroid and megakaryocytic cells carry enormous constitutive haem and iron demand — erythroid precursors alone account for the majority of whole-body haem synthesis — any erythroid or megakaryocytic character among KMT2A-rearranged cell lines would have supplied a trivial explanation for the selective haem-biosynthesis dependency this project found. Checking Cellosaurus line by line excluded that: **none of the 11 rearranged lines is erythroid or megakaryocytic, while eight such lines sit in the comparison group**, which pushes against the observed signal rather than creating it. Clinically, the branch is not entirely closed: KMT2A rearrangement accounts for about **7 percent** of paediatric non-Down-syndrome acute myeloid leukaemia with megakaryocytic differentiation, with worse outcomes than most other AMkL [E2].
Where the MEP sits and what it would be doing if it were healthy
The common myeloid progenitor faces a two-way choice. One branch is the GMP, making neutrophils and monocytes. The other is the MEP, making the two cell types that carry oxygen and stop bleeding: erythrocytes (red cells) and megakaryocytes (the giant polyploid cells that shed platelets). In humans all three sit in the lineage-negative CD34+CD38+ fraction and are separated by IL-3 receptor alpha and CD45RA; the MEP is the fraction negative for both 1.
The MEP's defining metabolic property is haem. A developing erythroblast must synthesise roughly a billion haemoglobin molecules, each carrying a haem group, and the erythroid lineage uses a dedicated erythroid-specific rate-limiting enzyme, ALAS2, rather than the housekeeping ALAS1. The erythroid compartment is the single largest consumer of iron and the largest site of haem synthesis in the body.
Why the absence of this lineage mattered to this project
ana-depmap-kmt2a-selective-scan-full found four iron and haem genes — ALAD (rank 14 of 17,728), IREB2 (15), UROS (41) and ALAS1 (47) — among the top selective requirements of KMT2A-rearranged leukaemia lines, and flagged the obvious alternative explanation in its own text: if any rearranged line has erythroid or megakaryocytic character, it will carry high haem demand for reasons that have nothing to do with the fusion.
Checking every line in Cellosaurus killed that version of the worry. None of the 11 rearranged lines is erythroid or megakaryocytic. Better than neutral, eight erythroid or megakaryocytic lines (HEL, HEL 92.1.7, SET-2, TF-1, F-36P, M-07e, CMK-11-5, OCI-M2) sit in the comparison group, so if anything they should have raised haem dependency on the other side of the contrast and suppressed the observed difference. The signal survived that.
This is a rare instance of a lineage entry earning its place by being absent, and it is the reason the monocytic alternative — which was not excluded — became the live question. See cell-type-monocyte and ana-kmt2a-r-line-panel-monocytic-audit.
The branch is narrow, not closed
KMT2A rearrangement is not absent from megakaryocytic leukaemia. In a Children's Oncology Group central-review series of 107 non-Down-syndrome paediatric AML with megakaryocytic differentiation drawn from AAML0531 and AAML1031, distinct fusions were identified in the majority: RBM15::MRTFA 20 percent, CBFA2T3::GLIS2 16 percent, NUP98 10 percent, KMT2A 7 percent, TEC::MLLT10 2 percent, MECOM 1 percent, FUS::ERG 1 percent. Cases with CBFA2T3::GLIS2 or KMT2A rearrangement had worse outcomes than other AMkL, while RBM15::MRTFA and AMkL with myelodysplasia-related changes fared better 2.
An earlier RNA and exome sequencing study of 99 AMKL specimens (75 paediatric, 24 adult) had already divided non-Down-syndrome AMKL into seven subgroups with varying outcomes, each characterised by a chimeric oncogene with cooperating epigenetic and kinase-signalling mutations, listing KMT2A rearrangements among the recurrent chimeric oncogenes 3.
So the correct statement is not that KMT2A fusions never enter the megakaryocytic branch; it is that they do so in a small minority of an already rare subtype, that no cell line in the standard panel represents it, and that when they do the outcome is poor.
| ontology | CL:0000050 |
|---|---|
| location | Bone marrow after birth; fetal liver before birth |
| immediate upstream | cell-type-cmp |
markers
[ "Lineage-", "CD34+", "CD38+", "IL3RA/CD123-", "CD45RA-" ]
lineage potential
[ "erythrocyte", "megakaryocyte and platelets" ]
immediate downstream
[ "cell-type-megakaryocyte" ]
kmt2a relevance
{
"depmap_control_value": "none of the 11 KMT2A-rearranged lines is erythroid or megakaryocytic while 8 such lines sit in the comparison group, which excluded the erythroid explanation for the selective haem-biosynthesis dependency",
"erythroid_megakaryocytic_comparison_lines": [
"HEL",
"HEL 92.1.7",
"SET-2",
"TF-1",
"F-36P",
"M-07e",
"CMK-11-5",
"OCI-M2"
],
"clinical_frequency": "KMT2A rearrangement in about 7 percent of paediatric non-Down-syndrome AML with megakaryocytic differentiation, with worse outcomes than most other AMkL",
"no_cell_line": "no KMT2A-rearranged megakaryocytic line exists in the standard panel, so this clinical subgroup has no model"
}atlas refs
[
{
"label": "Prospective isolation of human CMP, GMP and MEP",
"pmid": "12193648",
"title": "Prospective isolation of human clonogenic common myeloid progenitors.",
"authors": "Manz MG, Miyamoto T, Akashi K, et al.",
"venue": "Proc Natl Acad Sci U S A",
"year": 2002,
"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": "COG series of 107 paediatric AML with megakaryocytic differentiation",
"pmid": "36789545",
"title": "Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group.",
"authors": "Chisholm KM, Smith J, Heerema-McKenney AE, et al.",
"venue": "Pediatr Blood Cancer",
"year": 2023,
"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."
}
]- Because erythroid precursors are the body's largest consumers of haem and iron, any therapeutic aimed at the haem-biosynthesis dependency of KMT2A-rearranged cells would be expected to produce sideroblastic-type anaemia as its first and most predictable toxicity.
- The one clinical subgroup where KMT2A meets the megakaryocytic lineage has poor outcomes and no laboratory model, so it will be systematically invisible to preclinical programmes.
- Excluding the erythroid explanation for the haem signal removed the easiest alternative and left the harder one, so the apparent strength of the finding after that check is smaller than it looks.
- Why is the megakaryocyte-erythroid branch so nearly closed to KMT2A fusions? The answer would say something about which chromatin contexts the fusion can act in, and the question has not been asked directly.
- Do the roughly 7 percent of paediatric AMkL cases with KMT2A rearrangement respond to menin inhibition? No model exists, so the question is currently unanswerable in the laboratory and could only be approached from trial data.
- Given that eight erythroid/megakaryocytic lines sit in the DepMap comparison group, does removing them strengthen or weaken the haem signal? That re-analysis is free and has not been run.
- Is the erythroid-specific ALAS2 or the housekeeping ALAS1 the relevant enzyme in KMT2A-rearranged lines? The DepMap hit is ALAS1, which argues the dependency is not erythroid-type haem synthesis, and that point deserves to be made explicitly in the haem entries.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Human clonogenic common myeloid progenitors and their downstream granulocyte/macrophage and megakaryocyte/erythrocyte progenitors reside in the lineage-negative CD34+CD38+ fraction of adult bone marrow and cord blood and are prospectively separable by IL-3 receptor alpha chain and CD45RA expression, with the MEP negative for both.
Prospective isolation of human clonogenic common myeloid progenitors · Manz MG, Miyamoto T, Akashi K, Weissman IL · Proceedings of the National Academy of Sciences USA 2002What this evidence cannot show
Marker-based prospective isolation with in vitro clonogenic readout; purity is not absolute and the gates were defined in adult marrow and cord blood. Read: abstract only.
Evidence that argues against this (1)
- The CMP-to-MEP-or-GMP branch point does not hold as a general rule across development. Fetal liver contains many oligopotent progenitors with intermingled myeloid, erythroid and megakaryocytic fates while adult marrow contains almost none, and in adult marrow megakaryocyte-erythroid fate largely emerges directly from the stem-cell compartment rather than through a common myeloid intermediate. The MEP as a discrete adult compartment is therefore partly an artefact of the gating scheme. Read: abstract only. Notta F et al. 2016
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In a Children's Oncology Group central-pathology-reviewed series of 107 non-Down-syndrome paediatric AML with megakaryocytic differentiation from trials AAML0531 and AAML1031, distinct fusions were identified in the majority — RBM15::MRTFA 20 percent, CBFA2T3::GLIS2 16 percent, NUP98 10 percent, KMT2A 7 percent, TEC::MLLT10 2 percent, MECOM 1 percent, FUS::ERG 1 percent — and cases with CBFA2T3::GLIS2 or KMT2A rearrangement had worse outcomes than other AMkL.
Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group · Chisholm KM, Smith J, Heerema-McKenney AE, Choi JK, Ries RE, Hirsch BA, et al., Kahwash SB · Pediatric Blood and Cancer 2023What this evidence cannot show
AMkL is 5.5 percent of the parent trials' AML, so 7 percent of 107 is about 7 KMT2A-rearranged cases; outcome comparisons on that n are fragile and the two trials gave different 5-year EFS and OS overall. The KMT2A partner genes are not broken out. Read: abstract only.
Evidence that argues against this (1)
- Megakaryocytic differentiation is a minority route for KMT2A rearrangement, and the outcome signal may be driven by the comparator rather than by the lineage. In the same series NUP98-fusion AMkL also had poor outcomes in one of the two trials while RBM15::MRTFA and myelodysplasia-related AMkL fared better, so 'worse than other AMkL' reflects which fusions dominate the reference group. The broader landscape study divides non-Down-syndrome AMKL into seven subgroups with varying outcomes, which makes any two-way outcome comparison in this disease unstable. Read: abstract only. de Rooij JD et al. 2017
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
RNA and exome sequencing of 99 acute megakaryoblastic leukaemia specimens (75 paediatric, 24 adult) showed that paediatric non-Down-syndrome AMKL is heterogeneous and divides into seven subgroups with varying outcomes, characterised by chimeric oncogenes — including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements and NUP98-KDM5A — with cooperating mutations in epigenetic and kinase signalling genes.
Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes · de Rooij JD, Branstetter C, Ma J, Li Y, Walsh MP, Cheng J, et al., Gruber TA · Nature Genetics 2017What this evidence cannot show
Ninety-nine specimens split across seven subgroups leaves small per-group numbers, and the aetiology of 30-40 percent of AMKL cases remained unknown at the time. Adult and paediatric cases are pooled for sequencing but differ biologically. Read: abstract only.
Evidence that argues against this (1)
- Subgroup structure defined by chimeric oncogene does not settle cell of origin: AMKL is defined by blasts that morphologically resemble abnormal megakaryoblasts, which is a phenotype rather than a demonstrated MEP origin, and the COG series shows that morphology, cytogenetics and fusion status give partly discordant classifications with different outcomes. A KMT2A-rearranged AMkL case may be a KMT2A leukaemia wearing a megakaryocytic phenotype rather than a leukaemia of the MEP. Read: abstract only. Chisholm KM et al. 2023
- ← part ofCommon myeloid progenitor (CMP) — the fork at which KMT2A leukaemia almost always turns one way
MEP is the other branch downstream of the CMP gate
absence of erythroid/megakaryocytic character among rearranged lines excluded the erythroid explanation
KMT2A rearrangement in about 7 percent of paediatric AML with megakaryocytic differentiation
- related to →CBFA2T3::GLIS2, inv(16)(p13.3q24.3)
the dominant fusion of the same megakaryocytic subtype, with similarly poor outcomes
MEP is the immediate progenitor of the megakaryocyte
erythroid progenitor deferred because the KMT2A-relevant erythroid question is answered there
CD34 promotes erythroid differentiation at the expense of granulocyte and megakaryocyte lineages in primary human progenitors - a causal lineage-bias function, not a marker property
HEXIM1 is an essential transcription regulator during HUMAN erythropoiesis, controlling erythroid gene expression, proliferation and fetal globin (PMID 37738561)
zebrafish eaf1 deletion reduces erythropoiesis with loss of scl, lmo2 and gata1a expression and H3K27me3 gain at the gata1a promoter (PMID 37002435). Zebrafish, erythroid - four steps from this disease.
MEP is the BIPOTENT upstream progenitor and is the node HEXIM1 and EAF1 had to borrow; both results are about committed erythropoiesis with globin and gata1a readouts
high HOXA10 blocks erythroid and megakaryocyte development, while retroviral over-expression accumulates a megakaryocyte-colony-forming progenitor