Les mutations somatiques actives PTPN11 sont présentes dans environ 35 % des cas de LMMJ et définissent les plus...
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| ID | BMA-PTPN11-JMML |
|---|---|
| Type | Pertinence thérapeutique |
| État | reviewed 2026-05-04 | pending_clinical_signoff | actionability review required |
| Maladies | DIS-JMML |
| Sources | SRC-COG |
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| Biomarqueur | BIO-PTPN11 |
|---|---|
| Variante | mutation somatique active PTPN11 (E76K, D61G, Q79R) — JMML; CRITIQUE: distinguer somatique (JMML, nécessite HCT) vs germline/syndrome de Noonan (peut se résoudre à soi-même) |
| Maladie | DIS-JMML |
| Niveau ESCAT | IIIA |
| Combinaisons recommandées | azacitidine 75 mg/m2 SC jours 1 à 5 q28d — pont vers l'alloHCT dans la LMMJ; cycles multiples si nécessaire pour la réduction de la réponse/MRD, HCT allogénique (MRD10/MUD/haplo) — intention curative; PTPN11 somatique indique une urgence élevée pour le HCT, inhibiteur du SHP2 (RMC-4630, TNO155, ERAS-601) — investigationnel; cohortes d'expansion pédiatrique; essai clinique préféré |
| Résumé des faits | PTPN11 somatic activating mutations are present in ~35% of JMML cases and define the most common molecular driver of this disease. The mutation drives constitutive SHP2/ RAS/MAPK signaling. Allogeneic HCT is the only established curative treatment for JMML (5-year EFS ~50–55%). Molecular markers guide HCT urgency: somatic PTPN11 is associated with worse prognosis and shorter time to progression vs CBL or NRAS mutations. Azacitidine (5-day schedule) is used as bridge to HCT, with some evidence of responses (phase II: ORR ~20–30%) and MRD reduction pre-transplant. Investigational SHP2 inhibitors (RMC-4630, TNO155, ERAS-601) have JMML/pediatric expansion cohorts in phase I. MEK inhibitors (trametinib) also under evaluation in PTPN11-mutant JMML given downstream pathway convergence. ESCAT IIIA: somatic PTPN11 is prognostically relevant and the molecular target of SHP2 inhibitors in development; HCT remains standard; no approved SHP2 inhibitor. Germline PTPN11 (Noonan syndrome): different clinical entity — watch-and-wait approach often appropriate; HCT not usually needed for Noonan myelo... |
Notes
ESCAT IIIA: somatic PTPN11 in JMML is a validated prognostic biomarker and molecular target of investigational SHP2 inhibitors. HCT is the only proven curative option. CRITICAL CLINICAL DISTINCTION: Noonan syndrome-associated myeloproliferation (germline PTPN11) is typically self-limiting and does NOT require HCT — over-treatment with HCT in Noonan patients carries significant morbidity without benefit. Always confirm somatic vs germline origin of PTPN11 mutation before committing to HCT. Methods: compare tumor (bone marrow) vs germline (buccal swab/saliva) allele frequency; variant frequency >25–30% in bone marrow with homozygous loss suggests somatic with uniparental disomy. Post-HCT relapse: high (25–30%); salvage with second HCT or investigational agent. MRD monitoring by quantitative PCR for PTPN11 mutation pre/post HCT has predictive value for relapse risk.
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