ArticleBlood2014
PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML.
Article in Blood, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Targeting SHP2 phosphatase in hematological malignancies.Expert opinion on therapeutic targets · 2022Review
- Review
- T cell-specific constitutive active SHP2 enhances T cell memory formation and reduces T cell activation.Frontiers in immunology · 2022Article
- Pediatric Neoplasms Presenting with Monocytosis.Current hematologic malignancy reports · 2021Review
- The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.Experimental hematology · 2021Article
- Proteomic Analysis of an Induced Pluripotent Stem Cell Model Reveals Strategies to Treat Juvenile Myelomonocytic Leukemia.Journal of proteome research · 2020Article
- Frontline Science: TNF-α and GM-CSF1 priming augments the role of SOS1/2 in driving activation of Ras, PI3K-γ, and neutrophil proinflammatory responses.Journal of leukocyte biology · 2019Article
- Article
- Gain-Of-Function E76K-Mutant SHP2 Promotes Cell Proliferation, Metastasis, And Tumor Growth In Glioblastoma Through Activation Of The ERK/CREB Pathway.OncoTargets and therapy · 2019Article
- Article
- Role of SHP2 in hematopoiesis and leukemogenesis.Current opinion in hematology · 2017Review
- Turning the tide in myelodysplastic/myeloproliferative neoplasms.Nature reviews. Cancer · 2017Review
- Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations.Leukemia · 2017Article
- Article
- Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network.Nature genetics · 2015Article
- Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms.Molecular cancer · 2015Review
- Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP)--pure coincidence?European journal of human genetics : EJHG · 2015Article
- Identifying molecular features associated with psychoneurological symptoms in women with breast cancer using multivariate mixed models.Cancer informatics · 2015Article
- Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia.Haematologica · 2015Article
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12 authors at 4 institutions in 3 countries.
Funding
Abstract
Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110δ, but not PI3K p110α, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110δ-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110δ-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.