PTPN11/SHP2 - non-recurrent in infant KMT2A-rearranged ALL, well drugged everywhere else, and the one leukaemia trial that carried a SHP2 inhibitor was withdrawn
also called PTPN11 · SHP2 · SHP-2 · Shp2 · PTP2C · SHPTP2 · SH-PTP2 · SH-PTP3 · PTP-1D · PTP-2C · Q06124
PTPN11 makes SHP2, an amplifier that sits just upstream of the RAS switch, and drugs that block it exist. In infant KMT2A leukaemia it is mutated only occasionally - not in enough patients, and not in enough of each patient's cells, to be called a second driver - and there is currently no trial through which a child could receive a SHP2 inhibitor.
The same thing, for a scientist
PTPN11 (Q06124, 593 aa) encodes SHP2, the SH2-domain-containing tyrosine phosphatase that couples receptor tyrosine kinases to RAS. In infant KMT2A-rearranged ALL its status is precise and modest: **non-recurrent**. In the 22-case whole-genome discovery cohort it appears among the non-recurrent kinase/PI3K/RAS genes alongside FLT3, NF1 and PIK3R1, with KRAS (n = 4) and NRAS (n = 2) being the only recurrent ones [E1]; the same is true of the 20 non-infant MLL-R leukaemias in that study. It is detected again, at low cellular prevalence, in duplex-sequenced infant and childhood KMT2A-r ALL [E2]. In unselected paediatric B-ALL it is part of a co-occurring RAS-pathway set, correlated with NRAS mutation (phi 0.138, P = 0.0042) [E3], and in a high-risk paediatric leukaemia series NRAS, NF1 and PTPN11 together define a hyperactive-RAS group with inferior event-free and overall survival [E4]. **The therapeutic asymmetry is the point of this entry.** SHP2 is among the better-drugged nodes in the RAS pathway, with allosteric inhibitors in adult oncology. In leukaemia the registry shows the opposite of opportunity: the one registered protocol including a SHP2 inhibitor (ERAS-601) in haematological malignancy was **withdrawn**, with the registry reason **'Sponsor decision.'**, at a minimum age of 18 [E5]. A druggable node with no route to the patient is not a therapeutic option, and this graph should say so rather than list SHP2 among the opportunities.
This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.
I have never read one of these pictures before
A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.
Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.
Anything in yellow sticks is a bound small molecule, which is usually the drug.
Accession resolution
gene_exact:PTPN11 AND organism_id:9606 AND reviewed:true, with gene_primary and length:
| accession | primary | synonyms | protein name | length |
|---|---|---|---|---|
| Q06124 | PTPN11 | PTP2C SHPTP2 | Tyrosine-protein phosphatase non-receptor type 11 (SHP-2) | 593 |
One row, primary name matches. Note the protein-name field contains SH-PTP2, SH-PTP3, PTP-1D and PTP-2C - four historical names, two of which (SH-PTP2/SH-PTP3) differ by one digit and were used for this same protein in the early 1990s literature. This is a rule-65 shape in its milder form: the protein names are confusable with each other, but not with a different gene's, so reading the name back is safe here. Accession and length are asserted so verify-accessions.py can catch a swap.
Domains are taken from the UniProt feature table fetched the same day: SH2 1 at 6-102, SH2 2 at 112-216, and the tyrosine-protein phosphatase domain at 247-517.
Why 'non-recurrent' is a finding and not a shrug
The phrase does specific work. In the St. Jude cohort 1, the genes were sorted into recurrent (KRAS, NRAS) and non-recurrent (FLT3, NF1, PTPN11, PIK3R1) within a category - kinase/PI3K/RAS - that was itself present in 47% of cases. So PTPN11 is a member of a frequently hit pathway and an infrequently hit gene, and the two statements are routinely collapsed when a pathway-level entry stands in for gene-level ones.
That collapse has a therapeutic consequence. A patient is not treated with a pathway inhibitor because 47% of patients have something in the pathway; they are treated because they have a lesion a specific drug engages. For SHP2 inhibition the relevant number is the PTPN11 mutation rate in this disease, and that number is small, not measured precisely in any infant KMT2A-r cohort, and - in the one cohort that looked below the NGS floor - present at low cellular prevalence 2.
A recorded gap, not an absence. No published study reports a PTPN11 mutation frequency for infant KMT2A-rearranged ALL as its own number. The searches run for this entry that would have found one are listed in ana-cooperating-lesion-enumeration-kmt2a-r.
SHP2 chemistry exists; the route to these patients does not
The registry position, checked against the raw ClinicalTrials.gov v2 API on 2026-09-20 rather than through a wrapper that omits whyStopped:
| NCT | agents | condition | min age | status | whyStopped |
|---|---|---|---|---|---|
| NCT05279859 | ERAS-007, ERAS-601, gilteritinib | haematologic malignancies | 18 y | WITHDRAWN | 'Sponsor decision.' |
| NCT05658640 | trametinib + dexamethasone + cyclophosphamide + cytarabine | relapsed/refractory paediatric haematological malignancy | 1 y | recruiting | - |
Two things follow. First, the only paediatric route into RAS-pathway inhibition in leukaemia today is downstream of SHP2, at MEK, and its age floor is above this disease's modal age. Second, the SHP2 protocol stopped for a commercial reason, not a safety or efficacy one - which means the absence of SHP2 data in leukaemia is an absence of attempt, and the reopening condition is a sponsor decision rather than a scientific result.
This is the ChEMBL-scope caution in a different register: a target's tractability and a patient's access are independent facts, and the graph has repeatedly conflated them.
| uniprot | Q06124 |
|---|---|
| gene symbol | PTPN11 |
| length AA | 593 |
| alphafold ID | AF-Q06124-F1 |
| cytoband | 12q24.13 |
| resolution note | gene_exact:PTPN11 AND organism_id:9606 AND reviewed:true with fields=accession,gene_primary,gene_synonym,protein_name,length returned one row: Q06124, primary gene name PTPN11, 593 aa. Fetched from the UniProt REST API on 2026-09-20. Domain coordinates taken from the same record's feature table on the same day. |
| druggability | SHP2 is one of the better-drugged nodes in the RAS pathway in adult oncology (allosteric inhibitors binding a tunnel between the N-SH2, C-SH2 and PTP domains). In leukaemia the access position is the opposite of the chemistry position: the one registered haematology protocol carrying a SHP2 inhibitor was withdrawn for a sponsor decision at an 18-year age floor, so there is currently no route by which a child with this disease could receive one. |
domains — the numbers behind the chart
[
{
"name": "SH2 1 (N-terminal SH2)",
"start": 6,
"end": 102,
"pfam": null
},
{
"name": "SH2 2 (C-terminal SH2)",
"start": 112,
"end": 216,
"pfam": null
},
{
"name": "PTP (tyrosine-protein phosphatase)",
"start": 247,
"end": 517,
"pfam": null
}
]cooperating lesion profile
{
"disease": "infant KMT2A-rearranged B-ALL",
"status": "non-recurrent in the 22-case WGS discovery cohort; detected at sub-NGS cellular prevalence by duplex sequencing",
"gene_specific_frequency": "not reported by any published infant KMT2A-rearranged cohort - recorded gap",
"co_occurrence": "correlated with NRAS mutation in unselected paediatric B-ALL (phi 0.138)",
"verdict": "an infrequently mutated gene inside a frequently mutated pathway; the pathway rate must not be read as its rate"
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.6956,
"chronos_mean_other_leukaemia": -0.6898,
"difference": -0.0057,
"pan_essentiality_all_lines": -0.7304,
"selectivity_rank": 8402,
"rank_denominator": 17728,
"provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
"how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}- SHP2 is required for normal RTK signalling in developing tissues, and germline PTPN11 gain-of-function causes Noonan syndrome with cardiac, growth and haematological phenotypes. Pharmacological SHP2 inhibition in an infant is an intervention on a pathway that is actively building the child.
- A PTPN11 mutation in this disease is non-recurrent and, where measured at depth, sub-clonal - so a SHP2 inhibitor chosen on genotype would be aimed at a minority of the leukaemia in a minority of patients.
- The registry reason for the one withdrawn SHP2 leukaemia protocol is 'Sponsor decision.' A target whose clinical programme depends on a commercial decision is not a target the lab controls, and building a hypothesis on it means building on someone else's portfolio review.
- Blocking SHP2 upstream leaves every downstream activating lesion - KRAS, NRAS, BRAF - untouched, and those are the recurrent ones in this disease. A patient selected for RAS-pathway activation could have exactly the lesion a SHP2 inhibitor cannot reach.
- What is the PTPN11 mutation frequency in infant KMT2A-rearranged ALL specifically? No published cohort reports it as its own number, and the pathway-level 47% is routinely read as if it did.
- Would a SHP2 inhibitor do anything in a KMT2A-rearranged cell that is RAS-pathway wild-type? SHP2 sits upstream of RAS and is required for signalling through several receptors, so a benefit need not require a PTPN11 mutation - and that question has never been asked in this disease.
- Does SHP2 inhibition synergise with menin inhibition the way MEK inhibition was tested to? The MEK combination reduced burden without extending survival; whether the failure was the node or the pathway is untested.
- Are PTPN11 and NRAS mutations in the same patient in the same cell? The co-occurrence statistic cannot say, and the answer decides whether SHP2 inhibition would hit one clone or two.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In whole-genome sequencing of 22 infant MLL-rearranged ALL cases, PTPN11 was among the non-recurrent kinase/PI3K/RAS mutations (with FLT3, NF1 and PIK3R1), while only KRAS (n = 4) and NRAS (n = 2) were recurrent; PTPN11 was also non-recurrent among the 20 non-infant MLL-rearranged leukaemias in the same study.
The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. · Andersson AK, Ma J, Wang J, et al. · Nature Genetics 2015What this evidence cannot show
'Non-recurrent' in a 22-case discovery cohort means observed once; it is not a frequency estimate and a gene seen once in 22 could be present in several per cent of the disease. PTPN11 was on the 232-gene validation panel applied to 43 further cases, but the paper reports the validation result at pathway level (22/47) rather than per gene, so no gene-specific PTPN11 rate can be extracted from it. Full text read via efetch db=pmc (PMC4553269).
Evidence that argues against this (1)
- Duplex sequencing of the same disease detected PTPN11 among the recurrently altered genes at cellular prevalence below the standard NGS floor, so a gene called non-recurrent at 39x WGS is not thereby established as rare in the disease. Pilheden M et al. 2022
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Targeted duplex sequencing of 20 infants and 7 children with KMT2A-rearranged ALL identified PTPN11 among the genes recurrently altered in KMT2A-rearranged leukaemia, within a set of 87 cancer-implicated mutations of which 62% were below the resolution of standard NGS and only 33 exceeded 2% cellular prevalence.
Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia. · Pilheden M, Ahlgren L, Hyrenius-Wittsten A, et al. · HemaSphere 2022What this evidence cannot show
PTPN11 appears in the abstract's list of targeted genes found mutated; the abstract does not give a per-gene count or prevalence for PTPN11, so this entry does not state one. 27 patients, targeted panel. Abstract read; full text not retrieved.
Evidence that argues against this (1)
- The paper's own summary states that 31 of the 33 mutations above 2% cellular prevalence were in PI3K/RAS genes and 'typically KRAS/NRAS', which implies PTPN11's contribution sits mostly in the sub-2% fraction and therefore carries the least clonal weight of the pathway genes. Pilheden M et al. 2022
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In 488 paediatric B-ALL cases from CCCG-ALL-2015, NRAS and PTPN11 mutations were significantly correlated (phi = 0.138, chi-square 9.54, P = 0.0042), within a cohort where 39.3% carried at least one RAS-pathway alteration and RAS-pathway alterations as a class were not significantly associated with inferior survival.
The clinical relevance of RAS pathway gene mutations in childhood B-cell acute lymphoblastic leukemia. · Chen X, Gao L, Zhang Y, et al. · Annals of Hematology 2026What this evidence cannot show
Unselected paediatric B-ALL, single centre, retrospective, and variants called from whole-transcriptome sequencing so only expressed alleles are visible. The phi coefficient is small. Not an infant KMT2A-rearranged cohort, and the entry does not transfer the frequency to this disease. Abstract read.
Evidence that argues against this (1)
- A co-occurrence between two genes in the same linear pathway is usually read as cooperation, but in this disease it is at least as consistent with the two lesions occupying separate subclones: in the WGS cohort, 6 of the 8 cases with two or more pathway mutations had each mutation below 30% MAF. Andersson AK et al. 2015
- E4weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
In 43 paediatric ALL and AML patients with high-risk clinical features profiled by paired tumour/normal DNA sequencing and RNA-seq, RAS-pathway aberrations including N-RAS, NF1 and PTPN11 were frequent and associated with decreased event-free survival (22.8 vs 5.6 months, P = 0.04) and overall survival (124 vs 22.5 months, P = 0.04).
Mutations predictive of hyperactive Ras signaling correlate with inferior survival across high-risk pediatric acute leukemia. · Ney GM, Anderson B, Bender J, et al. · Translational Pediatrics 2020What this evidence cannot show
n = 43, single institution, ALL and AML pooled, and the cohort is explicitly selected for high-risk features (high white cell count, extramedullary disease, refractory or relapsed), so it cannot estimate frequency and its survival comparison is within an already-adverse group. PTPN11 is one of three genes pooled into the exposure. Graded weak because the design supports an association in a selected series and nothing stronger. Abstract read.
Evidence that argues against this (1)
- A 488-patient paediatric B-ALL cohort found RAS-pathway alterations as a class NOT significantly associated with survival, with the adverse signal confined to FLT3/NF1 co-mutation, so a pooled hyperactive-RAS exposure does not reproduce outside high-risk selection. Chen X et al. 2026
- E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
The only registered clinical protocol including a SHP2 inhibitor for haematological malignancy, a phase 1b/2 master protocol of MAPK-pathway agents including ERAS-601, was WITHDRAWN with the registry reason 'Sponsor decision.' and had a minimum enrolment age of 18 years.
A Phase 1b/2 Master Protocol of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Hematologic Malignancies · Erasca, Inc. · ClinicalTrials.gov 2022What this evidence cannot show
Retrieved from the raw ClinicalTrials.gov v2 API on 2026-09-20 because the MCP wrapper does not return whyStopped. 'Only registered protocol' is bounded by the query run: condition 'leukemia', intervention 'SHP2', which returned this single record. A SHP2 inhibitor entering a haematology trial under a compound code rather than the string 'SHP2' would not appear in that query, so this is a bounded absence and not a proof.
Evidence that argues against this (1)
- 'Sponsor decision.' is a commercial statement, not a scientific one. It carries no information about SHP2 inhibition's safety or efficacy in leukaemia, and it means the absence of data is an absence of attempt - so the reopening condition is a sponsor decision, not a result. Erasca et al. 2022
gene-level dossier: accession, domains, non-recurrence, and the withdrawn SHP2 protocol
one of the four RAS-pathway members the pathway-level entry summarises
- co-occurs with →NRAS - the other RAS, the one whose 0.3% clone came back, and a UniProt record that lists HRAS1 as its own synonym
correlated in paediatric B-ALL (phi 0.138, P = 0.0042)
- co-occurs with →KMT2A-rearranged acute lymphoblastic leukaemia
non-recurrent in the WGS discovery cohort; detected below the NGS floor by duplex sequencing
a Ptpn11 S502L activating mutation was acquired spontaneously in a ZM-alone murine AML (whole-exome sequencing)