Repurposing approved IMPDH inhibitors (mycophenolate, mizoribine, ribavirin) in KMT2A-rearranged leukaemia - cheap, mechanistically attractive, and asking an immunosuppressant of a neutropenic infant
also called mycophenolate mofetil repurposing · mycophenolic acid in MLL-fusion leukaemia · mizoribine · IMPDH inhibitor repurposing
The drugs that block IMPDH are already approved - they are the anti-rejection pills given after a transplant - so testing them in leukaemia would be fast and cheap. The catch is exactly what they were approved for: they switch off part of the immune system, and the patients here are babies whose immune systems are already flattened by chemotherapy.
The same thing, for a scientist
The repurposing case rests on three published strands. **(1)** AMLs with MLL-fusions are susceptible to IMPDH inhibitors in vitro, and alternate-day administration suppressed MLL-AF9-driven AML in vivo without devastating immune function, through TLR-TRAF6-NF-kB overactivation and VCAM1 upregulation; the accompanying commentary framed it explicitly as a repurposing proposal [E1][E2]. **(2)** IMPDH2 blockade lowers LEDGF and menin protein and sensitises MLLr AML to menin inhibitors [E3]. **(3)** Approved IMPDH inhibitors - mycophenolic acid and ribavirin - potentiate cytarabine in SAMHD1-proficient leukaemic cells by depleting the allosteric SAMHD1 activators GTP and dGTP [E4]. **Against this sits one directly relevant null:** a study designed to test the KMT2A link found sensitivity to IMPDH inhibitors **independent of KMT2A status** and absent in ALL cell lines [E5]. This entry therefore records a defensible combination proposal in myeloid disease with a named biomarker (SAMHD1), and it records that the unselected, KMT2A-enriched single-agent version of the idea has already been tested and did not hold.
The immunosuppression problem, stated properly
The repurposing argument's greatest strength is that the drugs are approved; its greatest weakness is what they are approved for. Mycophenolate mofetil and mizoribine are given to suppress lymphocyte proliferation in transplant recipients, and they do that by the exact mechanism proposed as antileukaemic: lymphocytes depend disproportionately on de novo guanine nucleotide synthesis because they lack a robust salvage pathway.
In an infant with KMT2A-rearranged ALL this collides with the clinical reality on four fronts:
- The patient is already profoundly immunosuppressed by induction chemotherapy, and infection is a leading cause of treatment-related mortality in infant ALL - a population in which treatment-related death competes with relapse as the dominant cause of failure.
- The infant immune system is developing. Prolonged suppression of lymphocyte proliferation in the first year of life is not equivalent to the same exposure in an adult transplant recipient, and the long-term immunological consequences are not characterised.
- The published in vivo result deliberately avoided the problem by using an alternate-day schedule chosen so as not to devastate immune function 1. That is a scheduling constraint discovered in mice, not a safety finding, and it means any trial inherits an intermittent schedule whose antileukaemic adequacy is unknown.
- The proposed combination partners make it worse. The cytarabine-potentiation route 4 adds an immunosuppressant to a myelosuppressive nucleoside analogue; the menin-inhibitor route 3 adds it to a drug whose own toxicity profile includes differentiation syndrome.
None of this makes the idea wrong. It makes the first trial a combination trial with an infection-focused safety run-in, not a single-agent expansion in babies.
Which version of the idea is actually supported
| version | supporting evidence | status |
|---|---|---|
| single agent, enriched for KMT2A-rearranged | 1 in vitro and mouse | contradicted by 5, which measured sensitivity as KMT2A-independent |
| combination with a menin inhibitor | 3, single laboratory, myeloid | mechanistically the strongest; never tested in a MEN1-mutant resistant line |
| combination with cytarabine, selected by SAMHD1 protein | 4, two independent 2026 studies | best-specified biomarker; explicitly negative in ALL cell lines |
| in infant KMT2A::AFF1 B-ALL | none | no supporting data in the index disease at all |
The last row is the one that matters for this graph. Every positive result is myeloid; the only lymphoid data are negative.
Why the cheapness argument is weaker than it looks
'Approved, therefore cheap to test' is true of the drug supply and false of everything else. A paediatric trial of an immunosuppressant in infants with leukaemia needs its own pharmacokinetics (mycophenolate exposure is notoriously variable and normally therapeutically monitored), its own infection-surveillance infrastructure, and a justification for adding immunosuppression to a regimen whose treatment-related mortality is already the co-dominant failure mode. In infant ALL the number of patients available worldwide is small enough that a trial slot spent here is a trial slot not spent on blinatumomab-like immunotherapy - and the immunological interaction between an IMPDH inhibitor and a T-cell-engaging therapy is antagonistic by construction.
That last point deserves emphasis. Infant KMT2A-rearranged ALL's most important recent advance is the addition of a T-cell-engaging antibody to chemotherapy. An agent whose approved indication is suppressing lymphocyte proliferation is the worst possible partner for it.
| target | gene-impdh2 |
|---|---|
| modality | small molecule, approved (repurposing) |
| approved indication | immunosuppression (transplant rejection prophylaxis, autoimmune disease); ribavirin as an antiviral |
| contradicted version | single agent enriched for KMT2A-rearranged disease - sensitivity measured as KMT2A-independent |
| evidence in index disease | none; the only lymphoid data are negative (ALL cell lines showed no synergy) |
| proposed biomarker | SAMHD1 protein in blasts at diagnosis - measurable today, never measured prospectively in paediatric KMT2A-rearranged disease |
| schedule constraint | the only in vivo antileukaemic result used ALTERNATE-DAY dosing specifically to limit immune suppression |
| trial design implication | combination trial with an infection-focused safety run-in; not a single-agent expansion in infants |
agents
[ "mycophenolate mofetil / mycophenolic acid", "mizoribine", "ribavirin" ]
supported versions
[ "combination with a menin inhibitor (myeloid, single laboratory)", "combination with cytarabine selected by SAMHD1 protein (AML, two studies)" ]
- The drug's approved purpose is to suppress lymphocyte proliferation. Giving it to an infant already neutropenic and lymphopenic from induction chemotherapy adds infection risk to a population in which treatment-related mortality competes with relapse as the leading cause of failure.
- It is mechanistically antagonistic with T-cell-engaging immunotherapy, which is the direction infant KMT2A-rearranged ALL treatment has actually been moving. A metabolic agent that disables the immune effector arm cannot be combined with the regimen it would have to be added to.
- Mycophenolate exposure is highly variable and normally therapeutically drug-monitored; a paediatric leukaemia trial inherits that whole pharmacokinetic burden, which erases much of the claimed cheapness of repurposing.
- Mycophenolate mofetil carries recognised reproductive toxicity with formal pregnancy-prevention requirements - not a constraint in infants, but a live one in adolescent and adult KMT2A-rearranged disease where the same argument would be made.
- The single-agent, KMT2A-enriched version of this idea has already been tested and the genotype link did not hold. A trial built on the 2023 framing rather than on the 2026 data would fail for a reason that is on the record today.
- What is SAMHD1 protein abundance in infant KMT2A::AFF1 blasts? If it is low, the best-specified version of this proposal is inapplicable to the index disease, and the measurement costs nothing.
- Does an IMPDH inhibitor retain activity against MEN1-mutant, menin-inhibitor-resistant leukaemia? That is the only clinical niche in which adding an immunosuppressant to an infant's regimen could be justified.
- Is there a dose and schedule that depletes guanine nucleotides in blasts without suppressing T-cell proliferation? The mouse answer was alternate-day dosing; no human pharmacodynamic study has asked this in leukaemia.
- Would an IMPDH inhibitor antagonise blinatumomab or CAR-T therapy in this disease? The mechanism says yes and nobody has measured it, and T-cell engagement is the most important recent advance in infant KMT2A-rearranged ALL.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Acute myeloid leukaemias with MLL-fusions are susceptible to IMPDH inhibitors in vitro; alternate-day administration of IMPDH inhibitors suppressed the development of MLL-AF9-driven AML in vivo without having a devastating effect on immune function; IMPDH inhibition induced overactivation of TLR-TRAF6-NF-kB signalling and upregulation of VCAM1, and combining IMPDH inhibitors with a TLR1/2 agonist effectively inhibited MLL-fusion AML development. The authors note that although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumour effects have not been proven in the clinical setting.
IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia. · Liu X, Sato N, Yabushita T, ..., Goyama S · EMBO Mol Med 2023What this evidence cannot show
Abstract read this session; author string copied from the fetched efetch record (first author Liu X, not Kazama H - an earlier entry in this graph carried the wrong name and it was corrected). Mouse MLL-AF9 and in vitro AML; no lymphoid, infant or human data. The 'without devastating immune function' claim is specific to an alternate-day schedule in mice and does not transfer to a child on cytotoxic chemotherapy. Drugs are pan-IMPDH, so the result belongs to IMPDH activity rather than to either paralogue. The proposed mechanism is a gain of TLR-NF-kB signalling from a nucleotide-depleting drug, which is indirect.
Evidence that argues against this (1)
- A study designed specifically to test the KMT2A link found IMPDH-inhibitor sensitivity independent of KMT2A status in AML cells and absent in ALL cell lines, with the operative modifier being SAMHD1 rather than the fusion. Klootsema Y et al. 2026
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
An accompanying commentary describes drug repurposing as offering shorter development timelines, low cost and reduced risk of failure, and frames the IMPDH-inhibitor result as providing a rational basis for repurposing IMPDH inhibitors for antileukaemia therapy, with the antileukaemia effect mediated at least in part through overactivation of TLR signalling and Vcam1 upregulation.
Repurposing immunosuppressants for antileukemia therapy. · Sezaki M, Huang G · EMBO Mol Med 2023What this evidence cannot show
Abstract read this session. This is a commentary on E1 in the same journal issue, not independent evidence; it is cited to establish how the field framed the result and to record the repurposing argument in its own words. It adds no data.
Evidence that argues against this (1)
- The commentary's own framing concedes the decisive point: the antitumour effects of IMPDH inhibitors have not been proven in the clinical setting. A repurposing argument that rests on regulatory convenience rather than on clinical evidence is a reason to test, not a reason to believe. Liu X et al. 2023
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Targeting IMPDH2 reduces guanine nucleotides and rRNA transcription, lowering LEDGF and menin protein, impairing MLL-fusion complex formation and chromatin binding; inhibition of guanine nucleotide biosynthesis or rRNA transcription further suppresses MLLr AML when combined with a menin inhibitor, providing a rationale to target guanine nucleotide biosynthesis to sensitise MLLr leukaemias to menin inhibitors.
Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition. · Shi X, Li M, Liu Z, ..., Nakada D · Nat Commun 2025What this evidence cannot show
Abstract read this session. Single laboratory, myeloid, no independent replication found 2026-09-20. The abstract does not state which IMPDH inhibitor was used or whether it was an approved agent, so the link from this mechanism to a repurposing proposal is an inference. No combination index, no resistant-line experiment and no in vivo combination endpoint are reported in the abstract.
Evidence that argues against this (1)
- An independent account of why IMPDH inhibition helps in AML runs entirely through ribosome biogenesis, TP53 stabilisation and MYC repression with no MLL complex in the picture, which would make the menin-sensitisation framing a correlate of reduced translation rather than the operative mechanism. Kawano G et al. 2026
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The approved IMPDH inhibitors mycophenolic acid and ribavirin imbalance deoxyribonucleoside triphosphate pools and increase cytarabine efficacy in SAMHD1-proficient but not SAMHD1-deficient leukaemic cells, by depleting the allosteric SAMHD1 activators and thereby preventing hydrolysis of the active metabolite ara-CTP.
IMPDH inhibition enhances cytarabine efficacy in SAMHD1-expressing leukaemia cells via guanine nucleotide depletion. · Yague-Capilla M, Dirks C, Eiden C, ..., Rudd SG · Mol Oncol 2026What this evidence cannot show
Abstract read this session. AML cell lines; the abstract makes no KMT2A claim, so this supports a repurposing route in AML generally rather than in the index disease. Ribavirin has documented activities beyond IMPDH, so the concordance of two drugs is weaker evidence than it appears. This is a chemosensitisation, not a single-agent effect, and cytarabine is not a mainstay of infant ALL induction.
Evidence that argues against this (1)
- The companion study found the same synergy absent in acute lymphoblastic leukaemia cell lines, which bounds the strategy away from the lymphoid index disease of this graph even where SAMHD1 is expressed. Klootsema Y et al. 2026
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Sensitivity to IMPDH inhibitors was independent of KMT2A status in AML cell lines and primary AML samples; synergy with cytarabine and fludarabine was SAMHD1-dependent and present in a subset of AML cells but absent in acute lymphoblastic leukaemia cell lines; the authors conclude that addition of IMPDH inhibitors to ara-C and F-ara-A may have therapeutic benefits in some AML cases.
Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia. · Klootsema Y, Tsesmetzis N, Sharma S, ..., Herold N · Cell Cycle 2026What this evidence cannot show
Abstract read this session. The KMT2A-independence finding is an absence of a detected difference in a panel of unstated size, not a demonstrated equivalence. Cell lines and primary samples with no in vivo arm. The paper's conclusion is deliberately narrow ('some AML cases'), and this entry should not be read as more enthusiastic than its own best-designed source.
Evidence that argues against this (1)
- The mechanism in E3 predicts benefit in combination with a menin inhibitor, not single-agent genotype-selective cytotoxicity, and a single-agent viability panel is not the assay that would detect it. The KMT2A-independence result therefore bounds one version of the repurposing proposal and leaves the combination version untested. Shi X et al. 2025
SAMHD1 proficiency is the measured effect modifier of IMPDH-inhibitor chemosensitisation
mechanistic rationale for the repurposing proposal
approved pan-IMPDH inhibitors: mycophenolate, mizoribine, ribavirin
in vitro susceptibility and in vivo suppression of MLL-AF9 AML development
the best-supported version of the proposal is combination with a menin inhibitor
- confers resistance to →Blinatumomab in infant KMT2A-rearranged ALL — the largest single outcome gain in thirty years
mechanistically antagonistic: an approved lymphocyte-proliferation suppressant against a T-cell-engaging therapy