Abstract
Numerous recurrent genetic mutations are known to occur in acute myeloid leukemia (AML). Among these common mutations, Fms-like tyrosine kinase 3 remains as one of the most frequently mutated genes in AML. We observed apparent marrow expansion of megakaryocytes in three out of six patients with Flt3-mutated AML following treatment with a recently FDA-approved Flt3 inhibitor, gilteritinib which possesses activity against internal tandem duplication and tyrosine kinase domain Flt3 mutations and also inhibits tyrosine kinase AXL. To assess whether biopsy findings can be attributed to promotion of megakaryocytic (Mk) differentiation with gilteritinib, we devised a cellular assay by overexpressing double mutated Flt3-ITDY591F/Y919F in chronic myeloid leukemia cell line K562 to study Mk differentiation in the presence of Flt3 and AXL inhibitors with non-mutually exclusive mechanisms. These experiments demonstrated the lack of direct effect Flt3 inhibitors gilteritinib and quizartinib on megakaryocytic differentiation at either transcriptional or phenotypic levels, and highlighted antileukemic effects of AXL receptor tyrosine kinase inhibitor and its potential role in megakaryocytic development.
Highlights
Fms like tyrosine kinase 3 (Flt-3), known as fetal liver kinase-2 (Flk2), is a receptor type tyrosine kinase encoded by the Flt3 gene
Seo and colleagues demonstrated that Wnt signaling inhibitor, Wnt-C59, and Flt3 inhibitor, TCS 359, significantly increased platelet-like particle production from Mk supporting the crucial role of Wnt signaling pathway and Flt3 in Mk development and maturation [5]
All patients ≥18 years old who had a diagnosis of acute myeloid leukemia with confirmed genetic status of Flt3 i.e. wild-type, Flt3-internal tandem duplication (ITD), or tyrosine kinase domain mutation (TKD) during 2019–2020 at the University of Wisconsin Hospitals and Clinics were included in the study
Summary
Fms like tyrosine kinase 3 (Flt-3), known as fetal liver kinase-2 (Flk2), is a receptor type tyrosine kinase encoded by the Flt gene. Flt3/Flk-2 ligand is a hematopoietic cytokine that plays an important role as a co-stimulatory factor in the proliferation, differentiation, and survival of hematopoietic stem and progenitor cells, including megakaryocyte/erythroid cells [1], and in the development of the immune system [2]. A Flt internal tandem duplication (ITD) mutation disrupts the autoinhibitory function of the receptor kinase domain, resulting in constitutive autophosphorylation of Flt. The duplicated sequences are mostly located in the juxtamembrane region, while the remaining are located in tyrosine kinase domain (TKD) [10, 11]
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