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The delta isoform of PI3K predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib
- Source :
- Exp Hematol
- Publication Year :
- 2021
-
Abstract
- Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the phosphatidylinositol-3-kinase (PI3K)-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro. Because CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor umbralisib as a single agent and in combination with the JAK1/2 inhibitor ruxolitinib, in CMML. Our ex vivo experiments with primary CMML patient samples revealed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT, and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data indicate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation.
- Subjects :
- Cell Survival
Class I Phosphatidylinositol 3-Kinases
Drug Synergism
Leukemia, Myelomonocytic, Chronic
Heterocyclic Compounds, 4 or More Rings
Article
Pyrimidines
hemic and lymphatic diseases
Cell Line, Tumor
Nitriles
Humans
Pyrazoles
Molecular Targeted Therapy
Phosphoinositide-3 Kinase Inhibitors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Exp Hematol
- Accession number :
- edsair.pmid..........6e6d07272d9e40c96b10db5fcc2ad343