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The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.
- Source :
-
Experimental Hematology . May2021, Vol. 97, p57-57. 1p. - Publication Year :
- 2021
-
Abstract
- • PI3k-δ is the most abundant PI3K subunit among monocytic leukemia samples. • CMML patient samples are uniquely sensitive to PI3K-δ inhibition by umbralisib. • Ruxolitinib and umbralisib synergistically decrease growth in CMML patient samples. • This combination can simultaneously suppress STAT5, ERK, S6, and AKT signaling. 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0301472X
- Volume :
- 97
- Database :
- Academic Search Index
- Journal :
- Experimental Hematology
- Publication Type :
- Academic Journal
- Accession number :
- 150020511
- Full Text :
- https://doi.org/10.1016/j.exphem.2021.02.008