LEDGF as a survival factor rather than a tether: it is upregulated in chemoresistant AML blasts, protects against daunorubicin, and knocking it down sensitises MLLr lines
also called LEDGF chemoresistance · LEDGF anti-apoptotic
LEDGF also helps leukaemia cells survive chemotherapy. Blasts from patients whose disease came back have more of it, and removing it makes cells easier to kill - which suggests a LEDGF drug would work best alongside chemotherapy rather than on its own.
The same thing, for a scientist
A strand of the LEDGF literature that predates the KMT2A work treats the protein as a stress-survival factor. Differential expression screening of blasts from patients with resistant relapsing AML against chemosensitive AML found **LEDGF/p75 the most consistently upregulated mRNA in resistant AML**, and transfection showed LEDGF/p75 and p52b antagonise daunorubicin-induced and cAMP-induced apoptosis - while p52 variants lacking exon 6 were **pro-apoptotic** and full-length p75 protected against a truncated pro-apoptotic p75. A later study reports LEDGF/p75-dependent chemoresistance in MLLr cell lines with effects on cell-cycle and survival pathways, and a link to BRD4 and MED1 super-enhancer coactivators. Taken with the PARP-inhibitor and etoposide sensitisation that LEDGF loss produces through its genome-maintenance functions, the convergent conclusion is that **the natural development path for a LEDGF-directed agent is combination with cytotoxic or PARP-directed therapy, not monotherapy** - and that lowers the potency bar, which matters given the micromolar ceiling on the only existing chemistry.
Three independent routes to the same combination prediction
- Direct anti-apoptotic function. LEDGF/p75 protects AML cells against daunorubicin in transfection, and is the most consistently upregulated transcript in chemoresistant relapsing AML blasts 1.
- Homologous recombination. LEDGF loss impairs CtIP recruitment and end resection and sensitises to etoposide 2.
- R-loop homeostasis. PSIP1 depletion sensitises cancer cells to PARP1 inhibitors and to R-loop-inducing DNA-damaging agents 3.
Three different laboratories, three different mechanisms, one direction. That is the kind of convergence this project's lab-independence instrument was built to check, and here it holds: the three have different last authors and no shared framework.
The MLLr-specific study adds a fourth route - LEDGF levels affect BRD4 and MED1 expression, both super-enhancer coactivators - but it could not be read beyond its abstract 4.
The isoform complication, again
The 2007 AML work is the clearest example of why concept-psip1-p52-is-not-p75 matters. Both p75 and p52b were protective; p52 variants lacking exon 6 were pro-apoptotic; and full-length p75 protected against truncated pro-apoptotic p75 1. An agent that lowers total PSIP1 output perturbs a system with internal opposition, and the net effect on apoptosis is not predictable from the total.
An agent that occupies a module - an IBD ligand - does something different again: it would not change the isoform ratio at all, and would leave the anti-apoptotic function intact if that function does not run through the IBD. Nobody has mapped the anti-apoptotic function to a domain.
What this reframing costs
Reading LEDGF as a chemosensitisation target rather than as a fusion tether is more consistent with the evidence, but it removes the axis's distinguishing claim. A chemosensitiser is judged against the other chemosensitisers available, does not need the KMT2A-selectivity argument that made the DepMap number exciting, and inherits the toxicity of the combination partner. It also means the target would be tested in combination from the start, which is harder to fund and slower to read out than a monotherapy signal in a xenograft.
The honest summary is that the chemosensitisation case is the better-supported one and the weaker one commercially, and the graph should hold both rather than letting the more exciting framing stand unopposed.
| phenotype | LEDGF supports survival under chemotherapy |
|---|---|
| independent last authors | 4 |
| implication | combination development path; lower potency bar than monotherapy |
| untested | PARP inhibitor plus LEDGF depletion in any KMT2A-rearranged model |
evidence routes
[ "direct anti-apoptotic (daunorubicin)", "homologous recombination (etoposide)", "R-loop homeostasis (PARP inhibitors)", "BRD4/MED1 super-enhancer coactivators" ]
- If the axis's real value is chemosensitisation, the normal-tissue consequence is chemosensitisation too, in a patient already at the tolerance limit of their cytotoxic therapy.
- LEDGF isoform variants have opposing effects on apoptosis, so an agent that lowers total protein could select for the protective species.
- A combination-only development path removes the monotherapy xenograft signal that this axis was being sold on, and makes the programme harder to fund and slower to read out.
- Does PSIP1 depletion sensitise a KMT2A-rearranged line to a PARP inhibitor, to etoposide, or to venetoclax? One plate, three drugs, and it would be the first combination datum on this axis.
- Which domain carries the anti-apoptotic function? If it is not the IBD, an IBD ligand would not deliver the chemosensitisation that is the best-supported part of the case.
- Is LEDGF upregulated in relapsed KMT2A-rearranged samples specifically? The 2007 AML finding was not fusion-stratified, and paired diagnosis-relapse expression data exist in public archives.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In differential gene expression screening of blasts from patients with resistant relapsing AML versus chemosensitive AML, LEDGF/p75 was the most consistently upregulated mRNA in resistant disease; transfection showed LEDGF/p75 and p52b antagonise daunorubicin-induced and cAMP-induced apoptosis in an AML cell line and in HEK-293, while LEDGF/p52 splice variants lacking exon 6 had pro-apoptotic effects and full-length LEDGF/p75 protected against truncated pro-apoptotic LEDGF/p75.
LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro. · Huang TS, Myklebust LM, et al. · Mol Cancer 2007What this evidence cannot show
Differential-display screening on pooled patient blasts with small numbers, followed by transfection overexpression rather than depletion. Not KMT2A-stratified. Open access in Europe PMC (PMC1876472).
Evidence that argues against this (1)
- Overexpression protecting against apoptosis does not establish that endogenous levels are limiting, and the opposing effects of different p52 variants in the same experiments show the system is not monotonic in total PSIP1. Huang TS et al. 2007
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
LEDGF loss impairs CtIP recruitment and DNA-end resection and increases sensitivity to etoposide, a second route by which removing LEDGF would sensitise leukaemic cells to standard cytotoxic therapy.
LEDGF/p75 Is Required for an Efficient DNA Damage Response. · Liedtke V, Schröder C, et al. · Int J Mol Sci 2021What this evidence cannot show
An engineered cell line, not leukaemic. Open access (PMC8198318).
Evidence that argues against this (1)
- Etoposide sensitisation in a LEDGF-null cell is an on-target toxicity in normal tissue as much as an efficacy mechanism in the tumour, and no experiment has compared the two. El Ashkar S et al. 2018
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
PSIP1 depletion increases the sensitivity of cancer cells to PARP1 inhibitors and to DNA-damaging agents that induce R-loop-dependent damage.
PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity. · Jayakumar S, Patel M, et al. · Nat Commun 2024What this evidence cannot show
Cancer cell lines, not leukaemic; the PARP inhibitor sensitisation has not been tested in any KMT2A-rearranged model. Open access (PMC10774266).
Evidence that argues against this (1)
- PARP-inhibitor sensitisation is a common consequence of any homologous-recombination perturbation and is not specific to LEDGF, so it does not distinguish this target from others. Daugaard M et al. 2012
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
LEDGF/p75-dependent chemoresistance is reported specifically in MLL-rearranged cell lines, with effects on cell-cycle and survival pathways, protection against apoptosis during chemotherapy, and altered expression of BRD4 and MED1.
LEDGF/p75-mediated chemoresistance of mixed-lineage leukemia involves cell survival pathways and super enhancer activators. · Canella A, Van Belle S, et al. · Cancer Gene Ther 2022What this evidence cannot show
Abstract only. Europe PMC returns no PMCID for this record (inEPMC N, isOpenAccess N), so the cell lines, knockdown depth and drug doses could not be checked and no claim beyond the abstract is made.
Evidence that argues against this (1)
- A knockdown that alters BRD4 and MED1 levels has systemic effects on transcription, so attributing the chemoresistance phenotype specifically to a LEDGF function rather than to a general transcriptional collapse is not possible from the abstract. Canella A et al. 2022
survival-factor function of this protein under chemotherapy
the R-loop route to the same combination prediction
the homologous-recombination route to the same combination prediction
LEDGF levels reported to affect BRD4 and MED1 expression
opposing isoform effects on apoptosis
- ← related toSUMO1 - not a complex partner of LEDGF but a modifier of it, and the interactome row cannot tell you which
an unexplored lever on LEDGF dose that does not touch the PWWP cage or the IBD