The Clinical impact of PTPN11 mutations in adults with acute myeloid leukemia

Alfayez, Mansour; Issa, Ghayas C.; Patel, Keyur P.; Wang, Rui; Wang, Xuemei; Short, Nicholas J.; Cortes, Jorge; Kadia, Tapan M.; Ravandi, Farhad; Pierce, Sherry; Assi, Rita; DiNardo, Courtney D.; Pemmaraju, Naveen; Kantarjian, Hagop M.; Borthakur, Gautam

doi:10.1038/s41375-020-0920-z

Cited by 44 publications

(62 citation statements)

References 28 publications

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“…Generally, PTPN11 mutations were detected with a frequency of 7%, which is in the range of prevalences (4%-12%) previously reported for AML. 1,25,26,[28][29][30] In line with published data, 26,[28][29][30] mutations predominantly affected the N-terminal SH2 domain of PTPN11, involved in basal inhibition of SHP2, [12][13][14][15] and were found at subclonal levels in most patients. 26 This is consistent with a predominance of RAS signaling gene mutations (eg, FLT3 TKD , NRAS, and KIT) as secondary or subclonal lesions in AML that ether emerge or are lost during clonal disease evolution.…”

Section: Discussionsupporting

confidence: 82%

“…1,25,26,[28][29][30] In line with published data, 26,[28][29][30] mutations predominantly affected the N-terminal SH2 domain of PTPN11, involved in basal inhibition of SHP2, [12][13][14][15] and were found at subclonal levels in most patients. 26 This is consistent with a predominance of RAS signaling gene mutations (eg, FLT3 TKD , NRAS, and KIT) as secondary or subclonal lesions in AML that ether emerge or are lost during clonal disease evolution. 1,37,38 The importance of individual PTPN11 variants (eg, E69K, G503A, and E76K), recurrently detected in our cohort, for RAS signaling hyperactivation, leukemic transformation, and chemoresistance in AML, has been summarized recently.…”

Section: Discussionsupporting

confidence: 82%

“…[21][22][23][24] More recently, the detection of PTPN11 mutations in adult patients with AML was associated with certain clinical features (ie, high rate of concomitant NPM1 mutations) and adverse prognosis (shorter overall survival [OS]). [25][26][27] In contrast, other recent reports did not observe a significant effect of PTPN11 mutations on outcome in AML 28,29 or, vice versa, an improved prognosis from the association with favorable genetic characteristics. 30 Hence, the clinical relevance of PTPN11 mutations in AML still remains controversial and needs further elucidation.…”

Section: Introductionmentioning

confidence: 71%

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Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

et al. 2021

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The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11 mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11 mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11 mutations were associated with concomitant mutations in NPM1 (63%), DNMT3A (37%), and NRAS (21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P < .001) and higher white blood cell counts (P = .007) compared with PTPN11 wild-type patients. In a multivariable analysis, PTPN11 mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P < .001), relapse-free survival (HR: 1.52; P = .013), and a lower rate of complete remission (odds ratio: 0.46; P = .008). Importantly, the deleterious effect of PTPN11 mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11 mutations (HR: 2.28; P < .001) but not found with dominant PTPN11 mutations (HR: 1.07; P = .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11 mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 71%

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Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

et al. 2021

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“…We found the NEST predicted risk score, age, TP53 mutation, ZRSR2 mutation, TET2 mutation, FLT3-ITD, and U2AF1 mutations were risk factors for a poor prognosis (Figure 8A), as reported by previous studies (6,19,(41)(42)(43)(44). In addition, the result suggested that PTPN11 mutation was a protective factor for CN-AML, which appeared to contrast with previous reports (45). We believe that the low PTPN11 mutation frequency among the BeatAML cohort could explain this discrepancy.…”

Section: Independence Of the Predicted Risk Scorecontrasting

confidence: 47%

Prognostic Prediction of Cytogenetically Normal Acute Myeloid Leukemia Based on a Gene Expression Model

et al. 2021

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Acute myeloid leukemia (AML) refers to a heterogeneous group of hematopoietic malignancies. The well-known European Leukemia Network (ELN) stratifies AML patients into three risk groups, based primarily on the detection of cytogenetic abnormalities. However, the prognosis of cytogenetically normal AML (CN-AML), which is the largest AML subset, can be hard to define. Moreover, the clinical outcomes associated with this subgroup are diverse. In this study, using transcriptome profiles collected from CN-AML patients in the BeatAML cohort, we constructed a robust prognostic Cox model named NEST (Nine-gEne SignaTure). The validity of NEST was confirmed in four external independent cohorts. Moreover, the risk score predicted by the NEST model remained an independent prognostic factor in multivariate analyses. Further analysis revealed that the NEST model was suitable for bone marrow mononuclear cell (BMMC) samples but not peripheral blood mononuclear cell (PBMC) samples, which indirectly indicated subtle differences between BMMCs and PBMCs. Our data demonstrated the robustness and accuracy of the NEST model and implied the importance of the immune dysfunction in the leukemogenesis that occurs in CN-AML, which shed new light on the further exploration of molecular mechanisms and treatment guidance for CN-AML.

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“…33,34 GOF mutations in exons 3 and 13 of PTPN11 are the main genetic cause of Noonan syndrome (NS) when germline, 35 or Juvenile myelomonocytic leukemia (JMML) when somatic 36 . In the context of MDS they occur mainly in children, 33,34 but are reported also in cases of acute leukemia 37,38 in adults as well 39,40 . All four mutations in our cohort were previously reported in JMML 41 and MDS patients 33,34 .…”

Section: Discussionmentioning

confidence: 67%

Pediatric myelodysplastic syndrome with inflammatory manifestations: Diagnosis, genetics, treatment, and outcome

Yanir

Krauss

Stein

et al. 2021

Pediatric Blood & Cancer

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Background Inflammatory manifestations (IM) are well described in adult patients with myelodysplastic syndrome (MDS), but the presentation is highly variable and no standardized treatment exists. This phenomenon is rarely reported in children. As more pediatric patients are hematopoietic stem cell transplantation (HSCT) candidates, the role of anti‐inflammatory treatment in relation to HSCT should be defined. Procedure Here, we report a series of five children from a tertiary center. We describe the clinical presentation, molecular findings, and treatment options. Results All patients presented with advanced MDS with blast percentages ranging 10–30%, all had severe IM. One patient had MDS secondary to severe congenital neutropenia, the other four patients had presumably primary MDS. All four were found to harbor a PTPN11 gene driver mutation, which is found in 35% of cases of juvenile myelomonocytic leukemia (JMML). The mutation was present in the myeloid lineage but not in T lymphocytes. Three had symptoms of Behcet's‐like disease with trisomy 8 in their bone marrow. All patients were treated with anti‐inflammatory medications (mainly systemic steroids) in an attempt to bring them to allogeneic HSCT in a better clinical condition. All demonstrated clinical improvement as well as regression in their MDS status post anti‐inflammatory treatment. All have recovered from both MDS and their inflammatory symptoms post HSCT. Conclusion Primary pediatric MDS with IM is driven in some cases by PTPN11 mutations, and might be on the clinical spectrum of JMML. Anti‐inflammatory treatment may reverse MDS progression and improve the outcome of subsequent HSCT.

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The Clinical impact of PTPN11 mutations in adults with acute myeloid leukemia

Cited by 44 publications

References 28 publications

Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

Prognostic Prediction of Cytogenetically Normal Acute Myeloid Leukemia Based on a Gene Expression Model

Pediatric myelodysplastic syndrome with inflammatory manifestations: Diagnosis, genetics, treatment, and outcome

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