Common lymphoid progenitor (CLP) — the CD10-positive lymphoid route that infant KMT2A leukaemia appears NOT to take
also called CLP · common lymphoid progenitor · Lin-CD34+CD10+CD24- lymphoid progenitor · CLP/early-B
The common lymphoid progenitor is the bone-marrow cell that has given up making myeloid cells and will become a B cell, a T cell or a natural killer cell. There appear to be two separate routes into B-cell development in humans, and the evidence points to infant leukaemia coming from the other one.
The same thing, for a scientist
The CLP (CL:0000051) is the lymphoid-restricted progenitor downstream of the multipotent and lymphoid-primed compartments. In human postnatal tissue the operational equivalent is a Lin-CD34+CD10+CD24-negative subset which has **very low myeloid potential**, generates B, T and NK lymphocytes, co-expresses RAG1, TdT, PAX5, IL7R-alpha and CD3-epsilon, circulates in blood throughout life and belongs to the most immature thymocyte population [E1]. Its relevance to this graph is a negative one that is sharper than most positives. Human B-cell development proceeds by **two layered pathways**: multipotent CD34+CD45RA+CD10-CD19- progenitors first generate a wave of PAX5-positive TdT-negative 'pre/pro-B' cells and later a wave of CD10-positive CLP/early-B cells, and these act as precursors for **distinct** pro-B cells; the authors identify the **PAX5+TdT-negative pre/pro-B pathway as the one that gives rise to infant B-lineage leukaemias**, in contrast to the CD10-positive early-B (B-2) pathway [E2]. This entry therefore defines the route that the disease appears to bypass, and complements `cell-type-fetal-preprob-cd10-negative`, which defines the route it takes.
What a CLP is and what it would be doing if it were healthy
Blood splits early into two great families: myeloid (red cells, platelets, granulocytes, monocytes) and lymphoid (B cells, T cells, NK cells). The common lymphoid progenitor is the cell at which that second family is settled: it can still choose among B, T and NK, but it has largely given up the myeloid options.
In humans the best-characterised postnatal equivalent is a subset of the CD34+CD10+ progenitor pool that is CD24-negative, which distinguishes it from cells already committed to B. These cells have very low myeloid potential, make B, T and NK lymphocytes, and already express the machinery of antigen-receptor assembly — RAG1 and terminal deoxynucleotidyl transferase (TdT) — alongside PAX5, the IL-7 receptor alpha chain and CD3-epsilon. They are found in cord blood, in bone marrow and in the blood throughout life, and they constitute the most immature thymocyte population, which identifies them as the cells that migrate from marrow to thymus to seed T-cell development 1.
So the healthy CLP's job is: commit to lymphoid, begin rearranging antigen receptors, and either stay in the marrow to make B cells or travel to the thymus to make T cells.
The CD10 question, and why it matters for infant leukaemia
CD10 (CALLA, neprilysin) has been used to define human lymphoid commitment for decades, and it is also the antigen after which common acute lymphoblastic leukaemia antigen is named. Two findings complicate it, and both bear directly on KMT2A-rearranged infant ALL.
First: there are two layered pathways into pro-B, and the infant leukaemia one is CD10-negative. Tracking the first ten generations of sorted cord-blood CD34-high lineage-negative progenitors in stromal co-culture with gene-expression profiling and immunoglobulin heavy-chain sequencing showed that multipotent CD34+CD45RA+CD10-CD19- progenitors generate an initial wave of PAX5-positive TdT-negative pre/pro-B cells and a later wave of CD10-positive CLP/early-B cells, and that these two act as precursors for distinct pro-B cells through two independent layered pathways. The authors align the PAX5+TdT-negative pre/pro-B pathway with the origin of infant B-lineage leukaemias, and the CD10-positive early-B pathway with the TdT-active B-2 lineage 2.
That is a direct statement that the CLP as classically defined is not the route infant KMT2A-rearranged leukaemia takes. It is also consistent with the well-known immunophenotype of infant KMT2A-rearranged B-ALL: CD10-negative pro-B.
Second: lymphoid priming begins before CD10 and the CD10-negative primed cell is not lymphoid-restricted. A CD10-negative CD62L-high population in human bone marrow is generated from HSCs before CD10 expression, sits transcriptionally between HSCs and Lin-CD34+CD10+ progenitors, and has full lymphoid and monocytic potential while lacking erythroid potential 3. So the cell immediately upstream of the CLP retains monocytic capacity — which is precisely the plasticity a KMT2A-rearranged B-ALL needs in order to lineage-switch to monocytic AML under CD19-directed therapy.
The T-cell arm
Because the CLP is also the thymus-seeding cell, it is the upstream of cell-type-early-t-precursor, and therefore the entry point for the KMT2A-rearranged T-ALL that this graph's T-lineage work rests on. Among 522 consecutively screened adult and paediatric T-ALLs, fusion transcripts were found in 20 percent, and patients with HOXA trans-deregulated T-ALL carrying MLLT10, KMT2A or SET fusions (17 percent, 39 of 235) had a worse prognosis: 5-year event-free survival 35.7 percent versus 63.7 percent. See cell-type-early-t-precursor for that analysis.
| ontology | CL:0000051 |
|---|---|
| location | Bone marrow, cord blood, and circulating in peripheral blood throughout life; seeds the thymus |
markers
[ "Lineage-", "CD34+", "CD10+", "CD24-", "CD19-", "RAG1+", "TdT/DNTT+", "IL7R+", "PAX5+" ]
lineage potential
[ "B cell", "T cell", "natural killer cell", "very low myeloid potential" ]
immediate downstream
[ "cell-type-pro-b", "cell-type-early-t-precursor" ]
kmt2a relevance
{
"route_not_taken": "infant B-lineage leukaemia is assigned to the CD10-negative PAX5+TdT- pre/pro-B pathway rather than the CD10-positive CLP/early-B pathway",
"immunophenotype_consistency": "infant KMT2A-rearranged B-ALL is characteristically CD10-negative pro-B",
"plasticity": "the stage immediately upstream of CD10 acquisition retains monocytic potential, which is the capacity a lineage switch to monocytic AML would exploit",
"t_arm": "the CLP is the thymus-seeding cell and therefore the entry point for KMT2A-rearranged T-ALL"
}atlas refs
[
{
"label": "Human postnatal circulating thymus-seeding lymphoid progenitor",
"pmid": "18070935",
"title": "A human postnatal lymphoid progenitor capable of circulating and seeding the thymus.",
"authors": "Six EM, Bonhomme D, Monteiro M, et al.",
"venue": "J Exp Med",
"year": 2007,
"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": "Two layered pathways into human pro-B",
"pmid": "20231472",
"title": "Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways.",
"authors": "Sanz E, Muñoz-A N, Monserrat J, et al.",
"venue": "Proc Natl Acad Sci U S A",
"year": 2010,
"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 the lymphoid progenitor immediately upstream of CD10 retains monocytic potential, a B-lineage-directed immunotherapy is attacking one output of a cell that has another, which is the structural reason lineage switch is available as an escape route rather than a rare accident.
- If infant KMT2A-rearranged B-ALL comes from a CD10-negative pathway, then CD10-directed diagnostics and any CD10-directed therapeutic would systematically miss it.
- The CLP circulates in blood and seeds the thymus, so a leukaemia arising in or near this compartment has access to a sanctuary site that marrow-directed therapy does not reach.
- Is the two-pathway model of human pro-B development reproducible with modern single-cell lineage tracing, and does KMT2A-rearranged infant B-ALL really map to the CD10-negative pathway rather than merely resembling it?
- Does the retention of monocytic potential at the CD10-negative CD62L-high stage explain why CD19-directed therapy in KMT2A-rearranged B-ALL so often produces monocytic disease rather than any other myeloid phenotype?
- Is CD10-negativity in infant KMT2A-rearranged B-ALL a marker of the pathway of origin, or a consequence of the fusion suppressing CD10? Distinguishing these would change how the immunophenotype is interpreted diagnostically.
- Are the CD10-negative CD62L-high population and the CD34+CD38-CD45RA+ multilymphoid progenitor the same cells? Two laboratories place monocytic potential at differently defined stages and the graph currently records both.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
A lymphoid-restricted human subset within the lineage-negative CD34+CD10+ progenitor population, distinguished from B-committed precursors by absence of CD24, has very low myeloid potential, generates B, T and natural killer lymphocytes, co-expresses RAG1, terminal deoxynucleotidyl transferase, PAX5, IL-7 receptor alpha and CD3-epsilon, is present in cord blood, bone marrow and blood throughout life, and belongs to the most immature thymocyte population.
A human postnatal lymphoid progenitor capable of circulating and seeding the thymus · Six EM, Bonhomme D, Monteiro M, Beldjord K, Jurkowska M, Cordier-Garcia C, et al., Andre-Schmutz I · Journal of Experimental Medicine 2007What this evidence cannot show
Postnatal human tissue with in vitro differentiation assays; 'very low myeloid potential' is an assay-dependent statement and the thymus-seeding role is inferred from phenotype sharing with the most immature thymocytes rather than demonstrated by tracking. Read: abstract only.
Evidence that argues against this (1)
- Lymphoid priming in human bone marrow begins BEFORE CD10 expression, in a CD10-negative CD62L-high population that sits transcriptionally between HSCs and Lin-CD34+CD10+ progenitors and has full lymphoid AND monocytic potential. Defining the CLP by CD10 therefore excludes the earliest lymphoid-primed cells and, more importantly for this graph, excludes a stage that retains monocytic capacity. Read: abstract only. Kohn LA et al. 2012
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Human B-cell development proceeds through two independent layered pathways: multipotent CD34+CD45RA+CD10-CD19- progenitors directly generate an initial wave of PAX5-positive TdT-negative pre/pro-B cells and a later wave of multilineage CD10-positive CLP/early-B cells, and these act as precursors for distinct pro-B cells; the PAX5+TdT-negative pre/pro-B differentiation pathway is the one that gives rise to infant B-lineage leukaemias, in contrast to the CD10-positive early-B (B-2) pathway.
Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways · Sanz E, Munoz-A N, Monserrat J, Van-Den-Rym A, Escoll P, Ranz I, et al., de-la-Hera A · Proceedings of the National Academy of Sciences USA 2010What this evidence cannot show
In vitro stromal co-culture of sorted cord-blood progenitors over ten generations, with the infant-leukaemia connection drawn by analogy to the mouse B-1a lineage rather than demonstrated in patient material. No KMT2A-rearranged sample is analysed. The two-pathway model is not universally accepted. Read: abstract only.
Evidence that argues against this (1)
- Assigning infant leukaemia to a particular normal B-cell pathway by transcriptional resemblance is exactly the inference that single-cell work in KMT2A-rearranged infant B-ALL warns against: mutation sharing across a B-ALL and its AML relapse in one child placed the rearrangement before haematopoietic specification, and that study states explicitly that cell of origin cannot be inferred from transcriptional state. The pre/pro-B route may be the state the blasts occupy rather than the path they took. Read: abstract only. Khabirova E et al. 2022
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
A CD10-negative CD62L-high progenitor population in human bone marrow is generated from haematopoietic stem cells before the onset of CD10 expression and before B-lineage commitment, has full lymphoid and monocytic potential but lacks erythroid potential, and sits at an intermediate stage of differentiation between HSCs and Lin-CD34+CD10+ progenitors; CD62L is expressed on immature thymocytes and its ligands are expressed at the thymic cortico-medullary junction.
Lymphoid priming in human bone marrow begins before expression of CD10 with upregulation of L-selectin · Kohn LA, Hao QL, Sasidharan R, Parekh C, Ge S, Zhu Y, et al., Crooks GM · Nature Immunology 2012What this evidence cannot show
Human bone marrow with in vitro lineage-potential assays and gene-expression profiling; potential measured in culture is an upper bound on what a cell does in vivo, and the thymus-homing role of CD62L is inferred from expression and ligand localisation rather than demonstrated by transfer. Read: abstract only.
Evidence that argues against this (1)
- The combined lymphoid-plus-monocytic potential described here had already been assigned to a differently defined compartment, the CD34+CD38-CD45RA+ multilymphoid progenitor, in a revised hierarchy in which macrophages and dendritic cells arise within early lymphoid development. Whether CD10-negative CD62L-high cells and multilymphoid progenitors are the same population under two marker schemes is not settled, so the stage at which monocytic potential is retained is defined differently by different laboratories. Read: abstract only. Doulatov S et al. 2010
the CLP is the lymphoid-restricted stage downstream of lymphoid priming
the CD10-positive CLP/early-B pathway feeds one of the two pro-B populations
the CD10-positive route contrasted with the CD10-negative route that infant leukaemia takes
the CLP circulates and seeds the thymus as the most immature thymocyte
osteoblast-derived CXCL12 maintains early lymphoid progenitors, which occupy an endosteal niche
Mef2c deficiency causes profound loss of common lymphoid progenitors alongside B, T and NK cells (murine; PMID 19169261)
SIRT1-deleted HSCs skew myeloid with a significant DECLINE IN THE LYMPHOID COMPARTMENT - directly relevant to a B-lineage disease, and measured in an animal with no fusion (murine; PMID 25068121)
REQUIRED IN: isolated Rybp-deficient common lymphoid progenitors give rise to increased B-1 progenitors in vitro, and LKS populations do the same (murine conditional knockout, normal adult haematopoiesis; PMID 26711264)
upstream progenitor; isolated RYBP-deficient CLPs gave rise to increased B-1 progenitors in vitro