PTPN11 mutations define a rare but highly adverse subset of myelodysplastic syndromes

PTPN11 encodes the protein SHP2 and acts as a stimulator of the RAS/MAPK pathway. Gain-of-function mutations in PTPN11 are associated with Noonan Syndrome, juvenile myelomonocytic leukemia (JMML), and hematological neoplasms.¹ In a study of 78 patients spanning the spectrum of myeloid neoplasms, PTPN11 mutations were associated with poor overall survival (OS), but this study included only 14 patients with myelodysplastic syndrome (MDS).² Therefore, the clinical and genetic characteristics of PTPN11-mutated (PTPN11mut) MDS require further evaluation.

To better characterize PTPN11mut MDS, we analyzed a cohort of 1,783 patients with newly diagnosed MDS (World Health Organization 2016) and available PTPN11 testing presenting to our center between 2011 and 2023. This study was approved by the institutional review board. PTPN11 mutations were rare and identified in only 30 (2%) patients. PTPN11 mutations were mostly located within the autoinhibitory N-SH2 domain (14/30, 47%) or PTPase (14/30, 47%) domain as previously described (Figure 1A).^1,3 Germline testing was not routinely performed, but this cohort did not include any known cases of Noonan Syndrome or RASopathy. The median age of the patients with PTPN11mut MDS was 67 years (range, 39-82) and eight (27%) had therapy-related disease. When compared to PTPN11-wild-type (PTPN11wt) patients, those with PTPN11 mutations were more likely to be female (70% vs. 35%; P<0.001), had lower baseline hemoglobin (median 9.0 vs. 9.4 g/dL; P=0.047), higher bone marrow blasts (median 9.5% vs. 4.0%; P<0.001), higher revised International Prognostic Scoring System (IPSS-R) scores (median 6.0 vs. 4.0; P=0.004), and were more likely to have IPSS-R very high-risk disease (47% vs. 25%; P=0.037) (Table 1). Although PTPNN11mut MDS had a higher frequency of IPSS-M very high risk compared to PTPN11wt, this was not statistically significant. There were no significant differences in sex distribution between the two PTPN11 mutation types. The most common cytogenetic findings in PTPN11mut MDS were -7/del(7q) (23%), normal cytogenetics (20%), del(5q) (17%), trisomy 8 (17%), and abnormal 3q (17%). The most common co-mutations were BCOR (5/16, 31%), RUNX1 (7/27, 26%), TET2 (7/27, 26%), SRSF2 (3/16, 19%), U2AF1 (3/16, 19%), and ASXL1 (5/27, 19%) (Figure 1B).

Figure 1.Genetic characteristics of PTPN11-mutated myelodysplastic syndrome. (A) Lollipop plot depicting PTPN11 mutations identified in this cohort. (B) Oncoprint depicting co-mutations present in ≥10% of patients, cytogenetic findings present in ≥10% of patients, bone marrow (BM) blast percentage, and revised International Prognostic Scoring System (IPSS-R) scores in patients with PTPN11-mutated myelodysplasticsyndrome. NA: not available.

The most common treatment consisted of hypomethylating agent (HMA)-based therapy in 15 (50%) patients, including six (20%) treated with HMA monotherapy and nine (30%) with HMA plus a second agent on clinical trial (either rigosertib, midostaurin, telaglenastat, ipilimumab, sabatolimab, durvalumab, magrolimab, or lenalidomide). The remaining patients received acute myeloid leukemia (AML)-type therapy, including intensive chemotherapy (high-dose cytarabine-based) in two (7%) patients, low-intensity chemotherapy (cladribine plus low-dose cytarabine) in two (7%) patients, and HMA plus venetoclax in one (3%) patient. Ten (33%) patients received best supportive care or unknown therapy. Seven (23%) patients underwent allogeneic stem cell transplantation (SCT) after a median of 5.0 months.

Eighteen (60%) patients were evaluable for response per the International Working Group (IWG) 2023 criteria. The overall response rate was 39% (7/18, consisting of 7 complete remissions [CR]). Interestingly, four of five (80%) patients treated with AML-type therapy achieved CR (1 FLAG-IDA, 2 cladribine/low-dose cytarabine, and 1 HMA plus venetoclax) compared to only three of 13 (23%) patients treated with HMA-based therapy. HMA responses were all with HMA-based doublets (combined with rigosertib in 1 patient, ipilimumab in 1 patient, and magrolimab in 1 patient). We observed no formal responses with single-agent HMA. There were no significant differences in the rate of CR between the two types of PTPN11 mutations (CR rate 20% with N-SH2 domain vs. 50% with PTPase domain mutations; P=0.3). The rate of AML transformation was four of 15 (27%) with HMA-based therapy and one of five (20%) with AML-type therapy (P>0.999). With a median follow-up time of 40.2 months, the median OS was 12.7 months in PTPN11mut MDS versus 25.6 months in PTPN11wt (MDS (P=0.015; Figure 2A). OS in PTPN11mut MDS (12.7 months) was similar to that of TP53mut MDS (11.5 months; P=0.173) and markedly worse than other high-risk MDS with PTPN11wt/TP53wt (26.2 months; P<0.01; Figure 2B). When matched 3:1 with controls matched for age, IPSS-R category, and TP53 status, the median OS was 12.7 months in PTPN11mut MDS versus 17.0 months in PTPN11wt MDS (P=0.22). When matched 3:1 using age, IPSS-M category (only available in 15 PTPN11mut patients), and TP53 status, the median OS was 13.8 in PTPN11mut MDS versus 19.9 months in PTPN11wt MDS (P=0.53).

Table 1.Baseline characteristics in PTPN11-mutated versus PTPN11-wild-type myelodysplastic syndrome.

We next performed subset analyses for OS within the PTPT-PN11mut cohort. When stratified by receipt of HMA-based (N=15) versus AML-type (N=5) therapy, the median OS was not significantly different between therapy types (median OS 12.7 months with HMA-based therapy vs. 16.5 months with AML-type therapy; P=0.38). There were no significant differences in OS when patients were stratified by PTPN11 mutation type (N-SH2 vs. PTPase domain), baseline blast %, or IPSS-R risk. The two patients with isolated PTPN11 mutations (no known co-mutations) were alive at a follow-up of 1.6 and 7.9 months, respectively. Therefore, although patient numbers were small, these subset analyses did not clearly identify a group of patients with favorable outcomes within the PTPN11mut cohort. Four of the six patients with PTPN11 mutations who survived beyond 2 years received allogeneic SCT, indicating an important role for this treatment modality.

We and others previously identified an adverse prognostic impact of PTPN11 mutations in AML.^4-6 A previous study suggested PTPN11 mutations may be similarly adverse in MDS (N=14).² Our present observations confirm and expand the findings of Swoboda and colleagues. PTPN11 mutations appear to be very rare in MDS (<2% of cases) but are associated with a highly adverse prognosis, both in terms of response rates and OS. We confirmed the association between PTPN11 mutations and female sex, increased bone marrow blasts, and higher IPSS-R risk as well as common co-mutations in BCOR, RUNX1, TET2, SRSF2, U2AF1, and ASXL1, similar to other reports.² Co-mutations in NPM1 and FLT3-internal tandem duplications appeared less common in our MDS cohort compared to PT-PN11mut AML.^4,6 Notably, abnormalities in chromosome 3q, generally rare events in MDS, appeared over-represented in our cohort, being identified in 17% of patients.

Although our patient numbers were too small for definitive conclusions, we noted increased response rates with AML-style therapy (80%) compared to HMA-based therapy (23%). Notably, no patients had a formal response to single-agent HMA as was also noted by Swoboda and colleagues.² This may be related to the fact that PTPN11 mutations activate the RAS/MAPK pathway, which is known to confer resistance to HMA, and may be more sensitive to cytarabine-based regimens.⁷, ⁸ However, the increased response rates with AML-type therapy did not translate to improved OS within the limitations of our small cohort. Importantly, most longterm survivors underwent allogeneic SCT.

A limitation of our study was the frequent co-occurrence of other adverse risk disease features with PTPN11 mutations, specifically RUNX1 mutations, monosomy 7/del(7q), and chromosome 3q abnormalities. The small size of our cohort precluded a multivariate analysis to elucidate the specific contribution of PTPN11 versus other factors on outcomes. We conclude that a proposed approach to PTPN11mut MDS may consist of more aggressive AML-type therapy and/or allogeneic SCT or treatment on a clinical trial, possibly with RAS pathway targeted therapies. Larger patient series are needed to establish the optimal therapy for PTPN11mut MDS.

Figure 2.Clinical outcomes of PTPN11-mutated myelodysplastic syndrome. (A) Overall survival from diagnosis in patients with PTPN11-mutated (PTPN11mut) versus PTPN11-wild-type (PTPN11wt) myelodysplastic syndrome (MDS). (B) Overall survival from diagnosis in PTPN11mut versus TP53mut MDS versus other high-risk (HR)-MDS.

Footnotes

• Received March 19, 2025
• Accepted June 12, 2025

Correspondence

A. BAZINET - abazinet@mdanderson.org

Disclosures

GMB discloses research funding from IFM Therapeutics, Rigel Pharmaceuticals, Jazz Pharmaceuticals, Daichii Sankyo, Stemline Therapeutics, and Salarius Pharmaceuticals. TK discloses grants from BMS, AbbVie, Amgen, Ascentage Pharma Group, Astellas Pharma, DrenBio, Astex, AstraZeneca, BMS, Celgene, Incyte, Cellenkos, Cyclacel, Delta-Fly Pharma, Genentech, Genfleet, Glycomimetics, Iterion, Janssen, Jazz Pharmaceuticals, Pfizer, Pulmotect, Regeneron, and SELLAS; consulting fees from AbbVie, Agios, Daiichi Sankyo, Genentech, Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Pulmotect, Sanofi-Aventis, and Servier; payment/ honoraria from AbbVie, Agios, Daiichi Sankyo, DAVA Oncology, DeltaFly, DrenBio, Genentech, Genfleet, Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, Rigel, Sanofi-Aventis, SELLAS, and Servier. CD discloses grants from AbbVie, Astex, ImmuneOnc, BMS, Cleave, Foghorn, Loxo, Rigel, and Servier; consulting fees from Amgen, AbbVie, Astellas, BMS, Genmab, GSK, Gilead, Jazz, Shrodinger, Servier, and Stemline; payment/honoraria from AbbVie, Astellas, BMS, Jazz, and Servier; travel support from Servier; participation on data safety board for Genmab. FR discloses clinical trial support from Astex and Taiho Oncology; payment/honoraria from Taiho Oncology. GGM discloses grants from Astex, Novartis, AbbVie, Genentech, Aprea, Curis, and Gilead; consulting fees from Astex, Acceleron, and BMS; payment/honoraria from Astex, Acceleron, AbbVie, Gilead, Curis, Genentech, and BMS. HK discloses grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, and Novartis; and payment/honoraria from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda. The remaining authors have no conflicts of interest to disclose.

Contributions

Funding

This work was supported in part by the University of Texas MD Anderson Cancer Center support grant CA016672.