Abstract 3499: The mutational status of residue Y842 in FLT3 predicts the drug response in acute myeloid leukemia

Abstract

Abstract The type III receptor tyrosine kinase FLT3 plays important roles in the development of early hematopoietic progenitor cells and is found to be mutated in around 35% of all cases of acute myeloid leukemia (AML). AML is a heterogeneous disease that affects the myeloid lineage of blood cells. Wild-type FLT3 needs its ligand, FL, for signal transduction. However, the oncogenic mutants are constitutively active even in the absence of ligand. Similar to the other type III receptor tyrosine kinases, such as KIT, CSF1R, PDGFRA and PDGFRB, ligand binding to the FLT3 induces dimerization, activation of the receptor and auto-phosphorylation. Tyrosine phosphorylation sites in FLT3 create docking sites for interacting proteins which transduce signals linked to survival and proliferation, among other things. Although the most common mutations in FLT3 includes the internal tandem duplication (ITD) mutations in the juxtamembrane domain of FLT3, point mutations in the kinase domain also occur. The so-called activation loop tyrosine residue is well conserved in all receptor tyrosine kinases and has long been known to be essential for the activity of some but not all receptor tyrosine kinases. Recently we have shown that activation loop tyrosine residue in KIT is not essential for its activation but plays an important role in regulating receptor stability and downstream signaling. The activation loop tyrosine residue in FLT3 (Y842) has been found to be mutated in some AML patients and acquired mutations of this residue results in drug resistance when combined with FLT3-ITD. We observed that different Y842 mutants (Y-to-F, Y-to-C and Y-to-H) display differential binding affinity for kinase inhibitors. Expression of Y-to-F mutant in myeloid cells resulted in impaired activation of ERK1/2 through reduced recruitment of SHP2 to the receptor. Furthermore, mice xenografted with myeloid cells expressing this Y-to-F mutant of FLT3, in FLT3-ITD background, resulted in delayed tumor formation. Gene set enrichment analysis (GESA) demonstrated that the Y-to-F mutation causes suppression of anti-apoptotic genes. Taken together, our data suggest that the activation loop tyrosine residue in FLT3 plays an important role in FLT3 downstream signaling and drug sensitivity. Citation Format: Julhash U. Kazi, Lars Rönnstrand. The mutational status of residue Y842 in FLT3 predicts the drug response in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3499.