PSIP1 is a tumour suppressor in the lymphoid lineage next door: losing Psip1 ACCELERATES T-ALL in mice, while the same protein is a dependency in KMT2A-rearranged myeloid leukaemia
also called PSIP1 dual role · LEDGF tumour suppressor T-ALL
In one kind of childhood leukaemia LEDGF is what the cancer needs. In the T-cell kind, mice that lose LEDGF get leukaemia faster, and patients' tumours carry loss-of-function mutations in it. A drug that removes LEDGF could help one disease and promote another.
The same thing, for a scientist
PSIP1, dispensable for normal haematopoiesis and a dependency factor in KMT2A-rearranged myeloid leukaemia, carries **loss-of-function mutations in T-ALL** that suggest a tumour suppressor role, and the mouse experiment agrees: **loss of Psip1 accelerated T-ALL initiation**, correlated with reduced H3K27me3 binding. The same paper reports the other half - loss of PSIP1 impaired proliferation in several T-ALL cell lines, through reduced COX20 and reduced mitochondrial respiration - and concludes PSIP1 exerts a dual role, tumour suppressor in initiation and dependency in maintenance. For this beat the finding is a first-class bite-back rather than a curiosity. Infant KMT2A-rearranged disease is overwhelmingly **B-lymphoid**, and every published in vivo demonstration that LEDGF is required for KMT2A-driven leukaemia is **myeloid** (MLL-ENL, MLL-AF9). The one lymphoid in vivo experiment on PSIP1 in leukaemia points the other way. That is not a reason to abandon the axis; it is a reason to run the lymphoid arm before believing the myeloid one generalises.
The two directions, in one paper
| Setting | PSIP1 manipulation | Effect |
|---|---|---|
| T-ALL initiation, mouse | Psip1 loss | accelerated leukaemia; reduced H3K27me3 binding |
| T-ALL maintenance, human cell lines | PSIP1 knockdown | impaired proliferation; reduced COX20; reduced mitochondrial respiration |
| Human T-ALL genetics | - | loss-of-function mutations present, consistent with tumour suppression |
| KMT2A-r myeloid leukaemia initiation, mouse | Psip1 knockout | blocked leukaemia |
The initiation/maintenance split here is the mirror image of the split this beat is built around. In KMT2A-rearranged disease the initiation arm is done and the maintenance arm is not; in T-ALL both are done and they disagree with each other in sign.
Why the lineage point is the sharp one
This project established in the same cycle that KMT2A-rearranged disease separates by lineage rather than by fusion across five independent axes, and that the sentence 'menin inhibition is differentiation therapy' is a myeloid sentence - in the lymphoid disease the same drug kills. The LEDGF literature has exactly the same structure and nobody has noticed: every in vivo KMT2A result is myeloid, and the only lymphoid in vivo PSIP1 leukaemia result is a tumour-suppressor result in a different lymphoid lineage.
So the load-bearing question for the infants is not the one the field has answered. It is: does PSIP1 behave as a dependency or as a suppressor in B-lineage KMT2A::AFF1 disease? No published experiment addresses it. The experiment in exp-psip1-inducible-knockdown-established-kmt2a-aff1-xenograft is built around a lymphoid model for exactly this reason.
The mechanism of the suppressor arm is not the mechanism of the dependency arm
The T-ALL acceleration correlates with reduced H3K27me3 binding, a polycomb readout - which converges with the finding that Psip1 loss abrogates Bmi1 and Ctbp1 recruitment at Hox loci and derepresses Hoxa and Hoxd, and with the 2026 brain knockout in which the differential expression signature was PRC2-dominated. Three independent systems now implicate a polycomb arm of LEDGF function, and in two of them removing LEDGF causes derepression.
The maintenance arm in T-ALL runs through something else entirely - COX20 and mitochondrial respiration - which is a fourth LEDGF function this graph had no entry for and which has no obvious relationship to chromatin tethering.
| kind | essential-function |
|---|---|
| severity | high for any systemic LEDGF-lowering agent used in a lymphoid disease |
| mechanism | PSIP1 loss accelerates T-ALL initiation in mice; loss-of-function PSIP1 mutations occur in human T-ALL |
| mitigation | run the B-lineage KMT2A::AFF1 maintenance experiment before committing; use an IBD-selective rather than a protein-lowering modality, since the tumour-suppressor arm has not been mapped to the IBD |
| lineage gap | all in vivo KMT2A LEDGF data are myeloid; the disease of interest is B-lymphoid |
affects
[ "gene-psip1", "exp-psip1-inducible-knockdown-established-kmt2a-aff1-xenograft" ]
- A systemic LEDGF-lowering agent is a candidate tumour promoter in the T-lineage, established in a mouse model and consistent with the human mutation spectrum.
- Paediatric patients cured of one leukaemia live long enough to develop a second one, and a drug that removes a lineage-specific tumour suppressor is exactly the class of agent for which that risk would not appear in any preclinical model used here.
- The dependency case rests entirely on myeloid models while the disease is lymphoid, and the only lymphoid in vivo leukaemia result on this gene points the other way.
- Is PSIP1 a dependency or a suppressor in B-lineage KMT2A::AFF1 disease? Nothing in the literature answers it and it is the load-bearing question for this project's patient population.
- Does the tumour-suppressor arm of PSIP1 depend on the IBD, the PWWP or neither? If it maps to a module a drug would not touch, the liability shrinks; nobody has separated them.
- Are PSIP1 loss-of-function mutations present in any KMT2A-rearranged cohort? If they occur at all in KMT2A-rearranged patients that would be direct evidence against the dependency model, and it is an archive query rather than an experiment.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
PSIP1 carries loss-of-function mutations in T-ALL suggesting a tumour suppressor role; loss of Psip1 accelerated T-ALL initiation in mice, correlating with reduced H3K27me3 binding; contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines through reduced COX20 and reduced mitochondrial respiration; the authors conclude PSIP1 has a dual role, tumour suppressor in initiation and dependency in maintenance.
A dual role for PSIP1/LEDGF in T cell acute lymphoblastic leukemia. · Demoen L, Matthijssens F, et al. · Sci Adv 2024What this evidence cannot show
T-ALL, not KMT2A-rearranged B-ALL. The acceleration is in a mouse model of T-ALL initiation and the H3K27me3 correlation is associative. Open access in Europe PMC (PMC11529709).
Evidence that argues against this (1)
- The same paper's maintenance result runs the other way - PSIP1 loss impairs proliferation of established T-ALL lines - so the tumour-suppressor finding does not straightforwardly predict that a LEDGF agent would promote lymphoid leukaemia in a patient who already has one. Demoen L et al. 2024
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Every published in vivo demonstration that LEDGF is required for KMT2A-driven leukaemia is myeloid: the conditional Psip1 knockout bone-marrow transplant used MLL-ENL, and the transformation and clonogenicity work used MLL-AF9.
LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis. · El Ashkar S, Schwaller J, et al. · Blood 2018What this evidence cannot show
This is a statement about the composition of the literature, verified by the counted queries in absence-ledgf-removal-from-established-kmt2a-leukaemia. The one in vitro human t(4;11) datum that exists is a mouse ESC TetR system, not a leukaemic cell.
Evidence that argues against this (1)
- The Psip1 conditional knockout also showed defects in B-cell production, so LEDGF is not irrelevant to the B lineage even though no B-lineage leukaemia experiment exists. El Ashkar S et al. 2018
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The polycomb arm implicated in the T-ALL acceleration converges with an independent finding that Psip1 loss abrogates Bmi1 and Ctbp1 recruitment at Hox loci and increases Hoxa and Hoxd expression.
Psip1/Ledgf p75 restrains Hox gene expression by recruiting both trithorax and polycomb group proteins. · Pradeepa MM, Grimes GR, et al. · Nucleic Acids Res 2014What this evidence cannot show
Different cell types and different polycomb complexes - Bmi1 is PRC1 and H3K27me3 is the PRC2 mark - so the convergence is thematic rather than mechanistic.
Evidence that argues against this (1)
- PRC1 and PRC2 readouts are not interchangeable, and treating a Bmi1 recruitment defect and an H3K27me3 binding change as the same observation would overstate the convergence. Debusschere L et al. 2026
tumour-suppressor arm of this gene in the T lineage
why the proposed experiment must include a lymphoid model
- related to →KMT2A-rearranged acute lymphoblastic leukaemia
the lymphoid disease in which this axis has never been tested
third system implicating a polycomb arm of LEDGF function