PTPN11 mutations are associated with poor outcomes across myeloid malignancies

Swoboda, David M; Ali, Najla Al; Chan, Onyee; Padron, Eric; Kuykendall, Andrew; Song, Jinming; Hussaini, Mohammad; Talati, Chetasi; Sweet, Kendra; Lancet, Jeffrey E.; Sallman, David A.; Komrokji, Rami

doi:10.1038/s41375-020-01083-3

Cited by 12 publications

(29 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, in our study, PTPN11-mut patients largely (57.8%) clustered within the ELN 2017 favorable risk category, mainly because of a high rate of associated NPM1 mutations (63%), which confirms recent reports on rates of NPM1 mutations (60.5%-61%) and the underlying cytogenetics in PTPN11-mut AML. 29,30 This is in conflict with other documentations, with a low rate (18%) 26 or absence (0%) 27 of favorable cytogenetics in PTPN11-mut AML, likely because of a lower frequency of concomitant NPM1 mutations (29% and 22%). 26,27 In addition to the cytogenetic context, previous work on PTPN11-mut AML varied considerably with respect to the age of PTPN11-mut patients at diagnosis (eg, 67-70 [25][26][27] vs ,60 years 29,30 ) and the respective treatment regimes (eg, high vs low intensity).…”

Section: Discussioncontrasting

confidence: 56%

“…29,30 This is in conflict with other documentations, with a low rate (18%) 26 or absence (0%) 27 of favorable cytogenetics in PTPN11-mut AML, likely because of a lower frequency of concomitant NPM1 mutations (29% and 22%). 26,27 In addition to the cytogenetic context, previous work on PTPN11-mut AML varied considerably with respect to the age of PTPN11-mut patients at diagnosis (eg, 67-70 [25][26][27] vs ,60 years 29,30 ) and the respective treatment regimes (eg, high vs low intensity).…”

Section: Discussioncontrasting

confidence: 56%

“…[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: 65%

“…[38][39][40] However, except for general similarities with respect to PTPN11 prevalences and some phenotypic and molecular features, no consensus has been reached for prognostic implications of PTPN11mut AML in the literature. [25][26][27][28][29][30] In part, this might be attributed to considerable differences in patients' characteristics (and numbers) of the analyzed cohorts. For example, in our study, PTPN11-mut patients largely (57.8%) clustered within the ELN 2017 favorable risk category, mainly because of a high rate of associated NPM1 mutations (63%), which confirms recent reports on rates of NPM1 mutations (60.5%-61%) and the underlying cytogenetics in PTPN11-mut AML.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 56%

Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…There are few published data regarding how PTPN11 mutations affect clinical outcomes. Hou et al 37 and Swoboda et al 35 have shown that patients with NPM1 wt /PTPN11 mut had reduced OS compared with patients with NPM1 wt /PTPN11 wt , and Alfayez et al 27 reported that PTPN11 mutations are associated with poor outcomes for both de novo and relapsed/refractory AML. Our current study validates these findings but also goes further by analyzing a larger cohort of patients, which allowed us to stratify the patients according to age.…”

Section: Discussionmentioning

confidence: 99%

Molecular, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia

Fobare¹,

Kohlschmidt

Özer

et al. 2022

Blood Advances

View full text Add to dashboard Cite

Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations impact outcomes of patients treated with intensive chemotherapy. We studied 1,725 newly diagnosed AML patients (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (i.e., FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes providing a rationale to study the biology and treatment approaches in this molecular group.

show abstract

The clinical features and prognostic implications of PTPN11 mutation in adult patients with acute myeloid leukemia in China

Yang,

Zhao,

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

BackgroundThe clinical significance of protein tyrosine phosphatase nonreceptor type 11 mutation (PTPN11mut) in acute myeloid leukemia (AML) is underestimated.MethodsWe collected the data of AML patients with mutated PTPN11 and wild‐type PTPN11 (PTPN11wt) treated at our hospital and analyzed their clinical characteristics and prognosis.ResultsFifty‐nine PTPN11mut and 124 PTPN11wt AML patients were included. PTPN11mut was more common in myelomonocytic and monocytic leukemia, and was more likely to co‐mutate with KRAS, KMT2C, NRAS, U2AF1, NOTCH1, IKZF1, and USH2A mutations than PTPN11wt. The overall survival for AML patients with PTPN11mut was significantly shorter than that for those with PTPN11wt (p = 0.03). The negative impact of PTPN11mut on overall survival was pronounced in the “favorable” and “intermediate” groups of ELN2017 risk stratification, as well as in the wild‐type NPM1 group (p = 0.01, p = 0.01, and p = 0.04).ConclusionPTPN11mut is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.

show abstract

PTPN11 mutations are associated with poor outcomes across myeloid malignancies

Cited by 12 publications

References 2 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

Molecular, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia

The clinical features and prognostic implications of PTPN11 mutation in adult patients with acute myeloid leukemia in China

Contact Info

Product

Resources

About