ArticleThe Journal of clinical investigation2014
Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 54 citations in OpenAlex.
- Exploiting an epigenetic resistance mechanism to PI3-kinase inhibition in leukemic stem cells.Leukemia · 2026Article
- Critical role of niche S100A8 for acute myeloid leukemia progression and hematopoiesis regeneration.Blood advances · 2025Article
- Article
- Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?Frontiers in pharmacology · 2024Review
- PI3-kinase deletion promotes myelodysplasia by dysregulating autophagy in hematopoietic stem cells.Science advances · 2023Article
- Mechanisms of resistance to targeted therapies for relapsed or refractory acute myeloid leukemia.Experimental hematology · 2022Review
- Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer.Molecular cancer research : MCR · 2022Article
- Membrane-bound SCF and VCAM-1 synergistically regulate the morphology of hematopoietic stem cells.The Journal of cell biology · 2021Article
- Review
- The Mevalonate Pathway, a Metabolic Target in Cancer Therapy.Frontiers in oncology · 2021Review
- Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment.Journal of controlled release : official journal of the Controlled Release Society · 2020Article
- PI3 kinase alpha and delta promote hematopoietic stem cell activation.JCI insight · 2019Article
- Rigosertib ameliorates the effects of oncogenic KRAS signaling in a murine model of myeloproliferative neoplasia.Oncotarget · 2019Article
- NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease.Oncogene · 2019Article
- Signaling Pathways in Leukemic Stem Cells.Advances in experimental medicine and biology · 2019Review
- PI3K: A Crucial Piece in the RAS Signaling Puzzle.Cold Spring Harbor perspectives in medicine · 2018Review
- Article
- Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations.Leukemia · 2017Article
- Article
- Article
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Authors and funding
14 authors at 5 institutions in 4 countries.
Funding
Abstract
The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system. Postnatal deletion of p110α resulted in mild anemia without affecting HSC self-renewal; however, deletion of p110α in mice with KRASG12D-associated JMML markedly delayed their death. Furthermore, the p110α-selective inhibitor BYL719 inhibited growth factor-independent KRASG12D BM colony formation and sensitized cells to a low dose of the MEK inhibitor MEK162. Furthermore, combined inhibition of p110α and MEK effectively reduced proliferation of RAS-mutated AML cell lines and disease in an AML murine xenograft model. Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML.
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