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BIOMARKER:

PTPN11 mutation

i
Other names: PTPN11, Protein Tyrosine Phosphatase Non-Receptor Type 11, Tyrosine-Protein Phosphatase Non-Receptor Type 11, Protein-Tyrosine Phosphatase 1D, Protein-Tyrosine Phosphatase 2C, SH-PTP2, SH-PTP3, PTP-1D, PTP2C, Protein Tyrosine Phosphatase Non-Receptor Type 11, Noonan Syndrome 1, METCDS, PTP-2C, SHPTP2, BPTP3, SHP-2, JMML, SHP2, Shp2, CFC, NS1
Entrez ID:
Related biomarkers:
8d
Refractory Chylothorax and Ventricular Hypertrophy Treated with Trametinib in a Patient with Noonan Syndrome: 18-Month Follow-Up. (PubMed, Children (Basel))
The patient demonstrated significant improvement in chylothorax and left ventricular hypertrophy, though pulmonary stenosis persisted. This case further confirms trametinib's potential as a therapeutic option for severe Noonan syndrome complications, emphasizing the need for further clinical trials to optimize treatment protocols and evaluate long-term outcomes.
Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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PTPN11 mutation
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Mekinist (trametinib)
25d
A prospective clinical study to evaluate the efficacy of dexitabine in maintenance therapy after hematopoietic stem cell transplantation in juvenile myelomonocytic leukemia (ChiCTR2400091166)
P=N/A, N=40, Not yet recruiting, The Seventh Affiliated Hospital, Sun Yat-sen University; The Seventh Affiliated Hospital, Sun Yat-sen University
New trial
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KRAS (KRAS proto-oncogene GTPase) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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KRAS mutation • NRAS mutation • NF1 mutation • PTPN11 mutation • CBL mutation
1m
ADVL1521: Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia (clinicaltrials.gov)
P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025
Trial completion date
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NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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NF1 mutation • RAS mutation • PTPN11 mutation • CBL mutation
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Mekinist (trametinib) • omipalisib (GSK2126458)
2ms
An Unexpected Finding of a PTPN11 Germline Mutation in a Patient With a Melanocytic Lesion With a Somatic MAP2K1 Mutation. Coincidence or Not? (PubMed, J Cutan Pathol)
As they are both part of the RAS-MAPK pathway. Furthermore, with the expansion of molecular diagnostics in melanomas, we expect to find an increase in unexpected (germline) mutations.
Journal
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MAP2K1 (Mitogen-activated protein kinase kinase 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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PTPN11 mutation
2ms
PTPN11 Mutation Clonal Hierarchy in Acute Myeloid Leukemia. (PubMed, bioRxiv)
This immune diversity was reconstituted from early precursor cells when engrafted into immunodeficient mice. Moreover, immune diversity was also observed in the blast component of patient samples with NPM1 and PTPN11 mutations, providing novel antigen targets for immune based approaches in this subset of AML that is resistant to multiple targeted therapies.
Journal
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NPM1 (Nucleophosmin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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NPM1 mutation • PTPN11 mutation • PTPN11 mutation + NPM1 mutation
2ms
Transient Myeloproliferative Disorder (TMD), Acute Lymphoblastic Leukemia (ALL), and Juvenile Myelomonocytic Leukemia (JMML) in a Child with Noonan Syndrome: Sequential Occurrence, Single Center Experience, and Review of the Literature. (PubMed, Genes (Basel))
After an initial response to antimetabolite therapy (6-mercaptopurine), she underwent haploidentical hematopoietic stem cell transplantation (HSCT) and is currently in complete remission. The goal of this review is to gain insight into the various hematological diseases associated with NS, starting from our unique case.
Review • Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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PTPN11 mutation
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mercaptopurine
7ms
STUDY OF THE MOLECULAR GENETIC PROFILE OF HIGH-RISK AML PATIENTS USING NEXT GENERATION SEQUENCING (EHA 2024)
Highly heterogeneous molecular genetic profile is present in patients from adverse risk group. Mutations ingenes that activate intracellular signaling pathways are most common in high-risk AML. The presence of morethan 6 mutations and ASXL1mut+ and SRSF2mut+ status negatively affect the survival of patients.
Clinical • Next-generation sequencing
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TP53 (Tumor protein P53) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • NF1 (Neurofibromin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • KMT2C (Lysine Methyltransferase 2C) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • FAT1 (FAT atypical cadherin 1) • CUX1 (cut like homeobox 1)
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TP53 mutation • DNMT3A mutation • ASXL1 mutation • PTPN11 mutation • SRSF2 mutation
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TruSight Myeloid Sequencing Panel
7ms
The elevation of red blood cell distribution width is an independent prognostic factor for juvenile myelomonocytic leukemia. (PubMed, Blood Sci)
RDW is an independent prognostic variable in JMML subjects. RDW may be regarded as an inexpensive biomarker to predict the clinical outcome in patients with JMML.
Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
PTPN11 mutation
8ms
Assessment of the FRET-based Teen sensor to monitor ERK activation changes preceding morphological defects in a RASopathy zebrafish model and phenotypic rescue by MEK inhibitor. (PubMed, Mol Med)
This work proves the usefulness of FRET imaging protocols on both live and fixed Teen ERK reporter fish to readily monitor and quantify pharmacologically- and genetically-induced ERK activity modulations in early embryos, representing a useful tool in pre-clinical applications targeting RAS-MAPK signaling.
Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
PTPN11 mutation
8ms
Next-generation sequencing reveals relapse and leukemia-free survival risks in newly diagnosed acute myeloid leukemia treated with CAG regimen combined with decitabine. (PubMed, Cancer Pathog Ther)
Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. NGS demonstrated a dismal overall outcome in patients with the rare PTPN11 mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.
Journal • Next-generation sequencing
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • GATA2 (GATA Binding Protein 2)
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FLT3-ITD mutation • IDH1 mutation • PTPN11 mutation
|
cytarabine • decitabine • aclarubicin
8ms
Unraveling trajectories from aplastic anemia to hematologic malignancies: genetic and molecular insights. (PubMed, Front Oncol)
Monosomy 7's prevalence and the occurrence of PTPN11 mutations suggest predictive and prognostic significance. Clonal evolution underscores the complexity of disease progression.
Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • KMT2C (Lysine Methyltransferase 2C)
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PTPN11 mutation • KMT2C mutation • MLL3 mutation
9ms
Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy? (PubMed, Front Immunol)
We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
PTPN11 mutation
9ms
FLT3-ITD mutation-positive acute myeloid leukemia undergoing clonal transition with PTPN11 mutation at relapse (PubMed, Rinsho Ketsueki)
The patient received gilteritinib monotherapy and achieved CR...He underwent related haploidentical peripheral blood stem cell transplantation but died of relapse. This was a case in which genetic analysis revealed clonal transition and acquisition of resistance to treatment.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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FLT3-ITD mutation • PTPN11 mutation
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Xospata (gilteritinib)
11ms
Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
PTPN11 mutation
11ms
Trial completion date • Trial primary completion date • Metastases
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NF1 (Neurofibromin 1) • AXL (AXL Receptor Tyrosine Kinase) • CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SMAD4 (SMAD family member 4) • RAF1 (Raf-1 Proto-Oncogene Serine/Threonine Kinase) • FLT1 (Fms-related tyrosine kinase 1) • CDK6 (Cyclin-dependent kinase 6) • CCND3 (Cyclin D3) • TYRO3 (TYRO3 Protein Tyrosine Kinase) • NTRK (Neurotrophic receptor tyrosine kinase)
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KRAS mutation • EGFR mutation • BRAF mutation • NRAS mutation • BRAF V600 • FGFR1 amplification • CDKN2A deletion • HRAS mutation • PTPN11 mutation • CCND1 amplification • KRAS amplification • BRAF amplification
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Mekinist (trametinib) • Tafinlar (dabrafenib) • Alecensa (alectinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • Kisqali (ribociclib) • Ayvakit (avapritinib) • siremadlin (HDM201)
12ms
Noonan Syndrome-related Myeloproliferative Disorder Occurring in the Neonatal Period: Case Report and Literature Review. (PubMed, J Pediatr Hematol Oncol)
Eight other cases of NS/MPD with neonatal onset are also summarized. The initial presentation varied, and the prognosis was considered poor compared with previous reports of NS/MPD.
Review • Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
PTPN11 mutation
1year
Analysis of Methylation Level and Clinical Characteristics of Juvenile Myelomonocytic Leukemia (ASH 2023)
high risk factors such as age at first diagnosis, PTPN11 mutation and compound mutation are significantly correlated with methylation in patients.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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KRAS mutation • NRAS mutation • NF1 mutation • ALK fusion • ALK mutation • PTPN11 mutation • CBL mutation
1year
Comprehensive Molecular Stratification of Patients with AML Treated with CPX-351 (ASH 2023)
Among patients with AML treated with CPX-351, PTPN11 and IDH2 mutations were independently associated with inferior overall survival compared to those without these mutations. The PTPN11 gene is involved in RAS pathway regulation and has also been associated with shorter survival in AML in other studies. Here, mutated SRSF2 was associated with improved survival after CPX-351 induction.
Clinical
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2)
|
TP53 mutation • FLT3-ITD mutation • IDH2 mutation • ASXL1 mutation • TET2 mutation • PTPN11 mutation • SRSF2 mutation
|
Vyxeos (cytarabine/daunorubicin liposomal formulation)
1year
RTK-RAS Signaling Pathway Was Enriched in Rare Acute Myeloid Leukemia Patients with t(16; 21)(p11; q22)/ FUS: : ERG (ASH 2023)
PTPN11 and NRAS were the most frequent mutations and RTK-RAS signaling pathway was the most involved pathway in rare AML patients with t(16; 21)(p11; q22)/ FUS: : ERG. The addition of signaling pathway inhibitors followed by HSCT might be an effective strategy to overcome the dismal outcome of this subtype. Larger cohort studies are warranted to investigate the molecular characteristics further as well as evaluate the clinical activity of the SHP2 (PTPN11) inhibitors in FUS: : ERG AML patients.
Clinical
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ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • BCOR (BCL6 Corepressor) • CD123 (Interleukin 3 Receptor Subunit Alpha) • NCAM1 (Neural cell adhesion molecule 1) • FUS (FUS RNA Binding Protein) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • SH2B3 (SH2B Adaptor Protein 3)
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KRAS mutation • NRAS mutation • DNMT3A mutation • RUNX1 mutation • RAS mutation • ASXL1 mutation • PTPN11 mutation • NRAS Q61 • BCOR mutation • NRAS G12
1year
Targeting Myeloid Epithelial Tyrosine Kinase (MERTK) Receptor in Acute Myeloid Leukemia Using a Novel Antibody Drug Conjugate, Rgx-019-MMAE (ASH 2023)
Finally, we investigated the synergistic effect of RGX-019-MMAE with Venetoclax (BCL2 inhibitor) or 5-Azacytidine in vitro. RGX-019-MMAE significantly induced cell death in AML cell lines and primary AML patient samples. RGX-019-MMAE, combined with chemotherapeutic agents and targeted therapy, produces a synergistic anti-leukemic effect. Our data indicates that MERTK is a potential therapeutic target in AML patients with monocytic subtypes of leukemia.
IO biomarker
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AXL (AXL Receptor Tyrosine Kinase) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • MERTK (MER Proto-Oncogene, Tyrosine Kinase)
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PTPN11 mutation • MERTK expression
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Venclexta (venetoclax) • azacitidine • RGX-019 • RGX-019-MMAE
1year
Clinical Characteristics and Prognosis of Acute Myeloid Leukemia Patients with Protein Tyrosine Phosphatase Non-Receptor Type 11 Gene Mutation (ASH 2023)
Our study suggests that PTPN11 VAF may not serve as a prognostic factor in patients with PTPN11 mut AML. However, newly diagnosed patients with high white blood cell count and poor performance status were identified as independent risk factors for EFS in PTPN11 mut AML.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • PTPN1 (Protein Tyrosine Phosphatase Non-Receptor Type 1)
|
FLT3-ITD mutation • PTPN11 mutation
1year
Clinical Characteristics and Prognosis of Acute Myeloid Leukemia Patients with Protein Tyrosine Phosphatase Non-Receptor Type 11 Gene Mutation. (PubMed, Pharmgenomics Pers Med)
Our study observed that PTPN11 VAF may not be a prognostic factor in patients with PTPN11 AML. Newly diagnosed high white blood cell count and poor performance status were independent risk factors for EFS in PTPN11 AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • PTPN1 (Protein Tyrosine Phosphatase Non-Receptor Type 1)
|
FLT3-ITD mutation • PTPN11 mutation
1year
Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations. (PubMed, Open Med (Wars))
Further analysis revealed no significant difference in OS among NPM1 /PTPN11 , NPM1 /PTPN11 , DNMT3A /PTPN11 , and DNMT3A /PTPN11 patients (p > 0.05). Multivariate analysis showed the proportion of bone marrow blasts ≥65.4% was a factor significantly affecting OS in PTPN11 patients (p = 0.043).
Journal
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • AFDN (Afadin, Adherens Junction Formation Factor)
|
NPM1 mutation • DNMT3A mutation • PTPN11 mutation
1year
Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape. (PubMed, Cancers (Basel))
Consistent with these data, assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, strongly suggesting their mis-regulated expression. Collectively, this study reveals histone modification pathways as an additional epigenetic abnormality in JMML patient HSPCs, thereby uncovering a new family of potential druggable targets for the treatment of JMML.
Journal
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PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
RAS mutation • PTPN11 mutation
1year
The clinical features and prognostic implications of PTPN11 mutation in adult patients with acute myeloid leukemia in China. (PubMed, Cancer Med)
PTPN11 is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.
Journal
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NPM1 (Nucleophosmin 1) • NOTCH1 (Notch 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • IKZF1 (IKAROS Family Zinc Finger 1) • KMT2C (Lysine Methyltransferase 2C) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • USH2A (Usherin)
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KRAS mutation • NRAS mutation • PTPN11 mutation • U2AF1 mutation • IKZF1 mutation • USH2A mutation
1year
A Clinical-Molecular Prognostic Scoring System for Myelodysplastic Syndrome in Asia – a Multicenter Study of the Asian Myeloid Working Group (AMWG) (ASH 2023)
Three-hundred and ninety-four patients (32.2%) received hypomethylating agents (azaciticine, N=367; decitabine, N=27), and 158 patients (12.9%) underwent allogeneic haematopoietic stem cell transplantation... Combining genomic with hematological and cytogenetic parameters, the Asian clinical-molecular prognostic model improved the risk stratification of patients with MDS in Asia, potentially improving clinical decision-making.
Clinical
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TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • GNAS (GNAS Complex Locus)
|
TP53 mutation • NRAS mutation • IDH2 mutation • NPM1 mutation • SF3B1 mutation • PTPN11 mutation • Chr del(5q) • GNAS mutation
|
decitabine
1year
Signaling Pathway Mutations Cooperate with the PICALM/MLLT10 Fusion in a Knock-in AML Mouse Model (ASH 2023)
We aim to functionally validate these findings by establishing mouse models that harbor the C/A fusion as well as mutations in Ptpn11 and other signal transduction genes. These murine models will be immensely valuable for gaining a deeper insight into PICALM/MLLT10-mediated leukemogenesis, studying cooperating mutations and for testing new targeted therapies.
Preclinical
|
KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • PAX5 (Paired Box 5) • IKZF3 (IKAROS Family Zinc Finger 3) • HOXA9 (Homeobox A9) • MEIS1 (Meis Homeobox 1) • SOX9 (SRY-Box Transcription Factor 9) • SPI1 (Spi-1 Proto-Oncogene) • GATA1 (GATA Binding Protein 1) • AFF2 (AF4/FMR2 family member 2) • ZEB1 (Zinc Finger E-box Binding Homeobox 1) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)
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KRAS mutation • PTPN11 mutation • CBL mutation • CD19 expression
1year
Efficacy of Demethylated Drug Combine with Low Dose Chemotherapy in Juvenile Myelomonocytic Leukemia (ASH 2023)
All patients were given Demethylated drug in combination with low-dose chemotherapy, 10 patients decitabine at a dose of 20 mg/m2 for 5 days, supplemented with cytarabine (50-100 mg/m2×3~5 days), and /or etoposide (50 mg/m2×3~5 days), 6 patients Azacytidine at a dose of 75mg/m2 for 7 days combined with homoharringtonine 2mg/m2 for 5-7 days. Demethylated drug in combination with low-dose chemotherapy could reduce JMML patients' tumor burden, improve the general condition, and obtain a clinical response rate of 81.8% after 3 cycles therapy. Therefore, such a combination regimen could be used as a therapeutic option for JMML before HSCT.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • JAK3 (Janus Kinase 3) • SETBP1 (SET Binding Protein 1) • SH2B3 (SH2B Adaptor Protein 3)
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KRAS mutation • NRAS mutation • ARID1A mutation • NF1 mutation • ASXL1 mutation • PTPN11 mutation • SRSF2 mutation • SETBP1 mutation • JAK3 mutation
|
cytarabine • azacitidine • etoposide IV • decitabine • Synribo (omacetaxine mepesuccinate)
1year
Overexpression of the Signaling Integrator Gab2 Accelerates AML Development in Mice with Dnmt3aR878H and Npm1cA Mutations (ASH 2023)
These data nominate GAB2 overexpression as a factor that may be relevant for the progression of founding clones with DNMT3A and NPM1 mutations to overt AML. Additional studies to define its protein interactome in preleukemic cells, its mechanism of action, and how leukemia-causing mutations in DNMT3A and NPM1 shape the fitness landscape to select for GAB2 overexpression are underway.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CD34 (CD34 molecule)
|
NPM1 mutation • KIT mutation • DNMT3A mutation • PTPN11 mutation • CBL mutation • DNMT3A mutation + NPM1 mutation • FLT3 expression • PAK1 overexpression
1year
Overcoming Venetoclax (Ven) Resistance through Glutamine (Gln) Depletion: Final Analysis of the Phase 1 Trial of Ven and Pegcrisantaspase (PegC) Combination in Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML) (ASH 2023)
We reported in vitro and in vivo depletion of Gln induced by long-acting Erwinia asparaginase, PegC, inhibited proliferation of complex karyotype (CK) AML and synergistically enhanced the antiapoptotic activity of Ven-mediated antagonism of Bcl-2 by decreasing the expression of proteins such as Mcl-1, whose translation is cap-dependent...Pt 31 (post-alloHSCT relapsed AML with FLT3-ITD) who had persistent disease after gilteritinib achieved an MRD-negative CRi, pending 2nd alloHSCT... VenPegC is a novel regimen that can induce complete remission in some heavily pretreated R/R AML patients, even with previous exposure to Ven. Pts with RUNX1 mutation, whose translation depends on pheIF4E, may benefit further from this regimen.
P1 data • IO biomarker
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • RUNX1 (RUNX Family Transcription Factor 1) • MCL1 (Myeloid cell leukemia 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CSF3R (Colony Stimulating Factor 3 Receptor) • EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)
|
TP53 mutation • NRAS mutation • RUNX1 mutation • RAS mutation • PTPN11 mutation • MCL1 expression • CSF3R mutation
|
Venclexta (venetoclax) • Xospata (gilteritinib) • Asparec (PEGylated recombinant Erwinia chrysantemi-derived L-asparaginase) • long-acting Erwinia asparaginase (JZP341)
1year
Review • Journal
|
PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
PTPN11 mutation
1year
Pharmacological strategies to overcome resistance in AML cell line models harboring activating FLT3-ITD and PTPN11 mutations (DGHO 2023)
Cells were exposed to sequential treatment of the glycosylation inhibitors tunicamycin or 2-deoxy-d-glucose in vitro, either with the HSP90 inhibitor 17-AAG, the STAT5 inhibitor pimozide or the MEK inhibitor trametinib. The presented Ba/F3 cell line experiments emphasize the potential impact of activating PTPN11 mutations in mediating multi-drug resistance. The combinational use of inhibitors targeting glycosylation and HSP90 represents a promising strategy to overcome resistance in FLT3-ITD mutated AML cells harboring activating PTPN11 mutations.
Preclinical
|
FLT3 (Fms-related tyrosine kinase 3) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • ANXA5 (Annexin A5)
|
FLT3-ITD mutation • PTPN11 mutation
|
Mekinist (trametinib)
1year
ADVL1521: Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia (clinicaltrials.gov)
P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> Sep 2024
Trial completion date
|
NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
NF1 mutation • RAS mutation • PTPN11 mutation • CBL mutation
|
Mekinist (trametinib)
over1year
Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC). (PubMed, Int J Mol Sci)
The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
KRAS mutation • KRAS wild-type • RAS wild-type • PTPN11 mutation
|
Aliqopa (copanlisib)
over1year
Role of SHP2 (PTPN11) in glycoprotein VI-dependent thrombus formation: Improved platelet responsiveness by the allosteric drug SHP099 in Noonan syndrome patients. (PubMed, Thromb Res)
Pharmacological inhibition of SHP2 by the allosteric drug SHP099 enhances GPVI-induced platelet activation under shear conditions with a potential to improve platelet functions of Noonan syndrome patients.
Journal
|
PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
PTPN11 mutation
|
SHP099
over1year
Myeloid sarcoma with NPM1 mutation may be clinically and genetically distinct from AML with NPM1 mutation: a study from the Bone Marrow Pathology Group. (PubMed, Leuk Lymphoma)
MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.
Journal
|
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
NPM1 mutation • DNMT3A mutation • PTPN11 mutation
over1year
Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes. (PubMed, Acta Neuropathol)
Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
Clinical data • Journal • Adverse events
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KRAS (KRAS proto-oncogene GTPase) • NF1 (Neurofibromin 1) • FGFR4 (Fibroblast growth factor receptor 4) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • RHEB (Ras Homolog, MTORC1 Binding)
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BRAF V600E • BRAF V600 • PTPN11 mutation
over1year
PHARMACOLOGICAL STRATEGIES TO OVERCOME RESISTANCE IN AML CELL LINE MODELS HARBORING ACTIVATING FLT3-ITD AND PTPN11 MUTATIONS (EHA 2023)
Background: Primary or secondary resistance towards various AML-treatment strategies like intensive chemotherapy, tyrosine kinase inhibitors or combination of the BCL-2 inhibitor venetoclax and hypomethylating agents can be mediated by activating mutations of the non-receptor phosphatase PTPN11 (SHP2) or by FLT3-ITD...Cells were exposed to sequential treatment of the glycosylation inhibitors tunicamycin or 2-deoxy-d-glucose in vitro, either with the HSP90 inhibitor 17-AAG, the STAT5 inhibitor pimozide or the MEK inhibitor trametinib... The presented Ba/F3 cell line experiments emphasize the potential impact of activating PTPN11 mutations in mediating multi-drug resistance and provide possible approaches of combined targeted therapies to overcome resistance. The combinational use of inhibitors sequentially targeting glycosylation and HSP90 as well as MEK- and STAT5 signaling represents a promising strategy in FLT3-ITD mutated AML cells harboring activating PTPN11 mutations.
Preclinical • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • ANXA5 (Annexin A5)
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FLT3-ITD mutation • PTPN11 mutation
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Venclexta (venetoclax) • Mekinist (trametinib)
over1year
HOMOHARRINGTONINE AND CYTARABINE COMBINED WITH VENETOCLAX (HAV) FOR ADULT PATIENTS WITH DE NOVO AML (EHA 2023)
Patients were treated with HHT 2-2.5mg/m2 on days 1-3 (d1-3) and cytarabine 100-200 mg/m2/d on d1-7 plus venetoclax 100mg/d on d1-14 (coadministration with oral Posaconazole 200mg three times a day). HAV was effective and well-tolerated in young adult patients with de novo AML, producing high rates of CR and encouraging OS and RFS. Acute myeloid leukemia
Clinical
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KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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FLT3 mutation • PTPN11 mutation
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Venclexta (venetoclax) • cytarabine • Synribo (omacetaxine mepesuccinate) • Noxafil (posaconazole)