FLT4 as a marker for predicting prognostic risk of refractory acute myeloid leukemia

• Type of Material: Article
• Authors: Ji Yoon Lee, Catholic University of Korea; Sung-Eun Lee, Catholic University of Korea; A-Reum Han, Catholic University of Korea; Jongeun Lee, Yonsei University; Young-sup Yoon, Emory University; Hee-Je Kim, Catholic University of Korea
• Language: English
• Date: 2023-06-15
• Publisher: Ferrata-Storti Foundation
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Ferrata Storti Foundation
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): https://doi.org/10.3324/haematol.2022.282472
• Title of Journal or Parent Work: Haematologica
• Volume: 108
• Issue: 11
• Start Page: 2933
• End Page: 2945
• Grant/Funding Information: This work was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant numbers 2017R1D1A1B03031406 and 2015R1D1A1A01059819); National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant numbers 2020R1A2C3003784, 2020M3A9I4038454 and 2021R1A2C1004571); the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (HI16C2211); and NHLBI (R01HL150887).
• Keywords: Fms-related tyrosine kinase 4; acute myeloid leukemia
• Research Categories: Biology, Molecular; Health Sciences, Oncology

Abstract

Treating patients with refractory acute myeloid leukemia (AML) remains challenging. Currently there is no effective treatment for refractory AML. Increasing evidence has demonstrated that refractory/relapsed AML is associated with leukemic blasts which can confer resistance to anticancer drugs. We have previously reported that high expression of Fms-related tyrosine kinase 4 (FLT4) is associated with increased cancer activity in AML. However, the functional role of FLT4 in leukemic blasts remains unknown. Here, we explored the significance of FLT4 expression in leukemic blasts of refractory patients and mechanisms involved in the survival of AML blasts. Inhibition or absence of FLT4 in AML blasts suppressed homing to bone marrow of immunocompromised mice and blocked engraftment of AML blasts. Moreover, FLT4 inhibition by MAZ51, an antagonist, effectively reduced the number of leukemic cell-derived colony-forming units and increased apoptosis of blasts derived from refractory patients when it was co-treated with cytosine arabinoside under vascular endothelial growth factor C, its ligand. AML patients who expressed high cytosolic FLT4 were linked to an AML-refractory status by internalization mechanism. In conclusion, FLT4 has a biological function in leukemogenesis and refractoriness. This novel insight will be useful for targeted therapy and prognostic stratification of AML.