@article{Peter P. Ruvolo_Huaxian Ma_Vivian R. Ruvolo_Xiaorui Zhang_Hong Mu_Wendy Schober_Ivonne Hernandez_Miguel Gallardo_Joseph D. Khoury_Jorge Cortes_Michael Andreeff_Sean M. Post_2017, place={Pavia, Italy}, title={Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS-like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms}, volume={102}, url={https://haematologica.org/article/view/8283}, DOI={10.3324/haematol.2017.168856}, abstractNote={Nearly one-third of patients with acute myeloid leukemia have FMS-like tyrosine kinase 3 mutations and thus have poor survival prospects. Receptor tyrosine kinase anexelekto is critical for FMS-like tyrosine kinase 3 signaling and participates in FMS-like tyrosine kinase 3 inhibitor resistance mechanisms. Thus, strategies targeting anexelekto could prove useful for acute myeloid leukemia therapy. ONO-7475 is an inhibitor with high specificity for anexelekto and MER tyrosine kinase. Herein, we report that ONO-7475 potently arrested growth and induced apoptosis in acute myeloid leukemia with internal tandem duplication mutation of FMS-like tyrosine kinase 3. MER tyrosine kinase-lacking MOLM13 cells were sensitive to ONO-7475, while MER tyrosine kinase expressing OCI-AML3 cells were resistant, suggesting that the drug acts <em>via</em> anexelekto in acute myeloid leukemia cells. Reverse phase protein analysis of ONO-7475 treated cells revealed that cell cycle regulators like cyclin dependent kinase 1, cyclin B1, polo-like kinase 1, and retinoblastoma were suppressed. ONO-7475 suppressed cyclin dependent kinase 1, cyclin B1, polo-like kinase 1 gene expression suggesting that anexelekto may regulate the cell cycle, at least in part, <em>via</em> transcriptional mechanisms. Importantly, ONO-7475 was effective in a human FMS-like tyrosine kinase 3 with internal tandem duplication mutant murine xenograft model. Mice fed a diet containing ONO-7475 exhibited significantly longer survival and, interestingly, blocked leukemia cell infiltration in the liver. In summary, ONO-7475 effectively kills acute myeloid leukemia cells <em>in vitro</em> and <em>in vivo</em&gt; by mechanisms that involve disruption of diverse survival and proliferation pathways.}, number={12}, journal={Haematologica}, author={Peter P. Ruvolo and Huaxian Ma and Vivian R. Ruvolo and Xiaorui Zhang and Hong Mu and Wendy Schober and Ivonne Hernandez and Miguel Gallardo and Joseph D. Khoury and Jorge Cortes and Michael Andreeff and Sean M. Post}, year={2017}, month={Nov.}, pages={2048-2057} }