Abstract 1681: Characterizing signaling and localization of Daple-FLT3 gene fusion in leukemia cells

Abstract

Abstract Receptor tyrosine kinases (RTKs) are cell surface receptors that regulate cell survival, cell proliferation, and cell migration upon ligand binding. Genetic mutations leading to hyperactivation of RTKs are often seen in cancer and allow signaling pathways to be constitutively active. In some hematological malignanices, the coiled-coil domain (CCD) of Daple, a cell signaling scaffold protein, has been found in gene fusions with the RTKs FLT3 and PDGFRB, and to the intracellular kinase JAK2. It is hypothesized that this gene fusion product causes the tyrosine kinase domain of FLT3 to become activated and mislocalizes in the cell, leading to rampant cell signaling of either the MAPK, AKT, and STAT5 signal transduction cascades. Using fluorescently tagged Daple-FLT3, it was shown that the gene fusion product is subcellularly localizes to the peri-centrosome space across all leukemia cell lines tested. Ectopic expression demonstrated activation of the kinase domain and subsequent increases in phosphorylation of STAT5α and AKT, but no significant increase in the phosphorylation of MAPK was observed. Further investigation is needed to identify direct substrates of the Daple-FLT3 gene fusion and transcriptional changes. Identifying the direct kinase substrates and insights gained through understanding the gene fusion localization, affects on cell signaling, and changes in gene expression, may unveil novel therapeutic strategies into targeting this protein in cancer. Citation Format: Michael Acquazzino, Jason Ear. Characterizing signaling and localization of Daple-FLT3 gene fusion in leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1681.