PTPN11 mutation

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.

P=N/A, N=40, Not yet recruiting, The Seventh Affiliated Hospital, Sun Yat-sen University; The Seventh Affiliated Hospital, Sun Yat-sen University

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

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.

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.

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.

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.

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.

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.

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.

Monosomy 7's prevalence and the occurrence of PTPN11 mutations suggest predictive and prognostic significance. Clonal evolution underscores the complexity of disease progression.

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.

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.

No abstract available

P2, N=425, Recruiting, Centre Leon Berard

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.

high risk factors such as age at first diagnosis, PTPN11 mutation and compound mutation are significantly correlated with methylation in patients.

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.

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.

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.

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.

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.

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).

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.

PTPN11 is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.

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.

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.

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.

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.

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.

No abstract available

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.

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> Sep 2024

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.

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.

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.

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.

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.

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