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

Abstract

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.

Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations

“…Additionally, we found mutations of PTPN11 to be significantly associated with the presence of EM AML while the odds for EM AML were significantly decreased in IDH2 - or CEBPA -mutated AML. PTPN11 has recently been described as an independent marker of poor outcome in AML [ 34 , 35 ] and has been associated with EM [ 36 ]. PTPN11 encodes for the Src homology region 2 domain-containing phosphatase-2 (SHP-2) which functions as a signal enhancer for cell growth and differentiation downstream of numerous intracellular pathways including RAS/ERK/MAPK, JAK/STAT as well as PI3K/AKT and FLT3 signaling therefore playing a critical role in leukemogenesis [ 37 – 41 ].…”

Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

“…TET2 mutations as well as alterations of IDH1/2, SF3B1, or DNMT3A represent positive predictors for response towards HMAs in MDS and AML [81][82][83][84]. On the other hand, mutations in ASXL1, PTPN11, CDKN2A, ETV6, and FLT3-ITD were associated with shorter OS and lower ORR [85,86]. In a large retrospective registry analysis of 311 patients, no significant differences between patients with TP53 wild type or mutations regarding response towards DEC could be detected.…”

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

“…AML patients with RAS or PTPN11 mutations, although not classified in the ELN classification system [ 4 ], showed decreased OS when treated with induction chemotherapy, with a median OS of 12 months for RAS-mutated AML patients and compared to 30.1 months for the other patients [ 93 ], and a median OS of 13.4 months for PTPN11-mutated AML patients compared to 19.2 months for wild-type PTPN11 AML patients [ 94 ]. In addition, when treated with venetoclax-based therapy, the presence of RAS mutations in newly diagnosed, relapsed and refractory AML patients is associated with poor response rates with CR/CRi rates of 0–36% compared to 23–64% for the total patient cohort, and a shorter median OS (3.8 months) compared to the patients with wild-type NRAS (7.4 months) ( Table 3 ) [ 37 , 48 , 54 ].…”