Fms-like tyrosine kinase 3 (FLT3) mutation is one of the most prevalent molecular abnormalities in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (FLT3-ITD) mutation being the major mutated form. AML patients with FLT3-ITD mutations have unfavorable outcomes with chemotherapy alone, while FLT3 inhibitors significantly improve patient prognoses. Recent studies have indicated that FLT3 mutated receptor has different intracellular localization of the protein, which can be specifically targeted. This review summarizes the different intracellular localization of FLT3 protein, and the influence of different positions on downstream signals. When the FLT3 receptor is located on the cell membrane, it mainly activates the downstream RAS/MAPK signaling pathway. However, the FLT3 protein located in the endoplasmic reticulum (ER) mainly activates the STAT5 signaling pathway. The wild-type FLT3 receptor is mainly located on the cell membrane, and the FLT3-ITD receptor is mainly located in the endoplasmic reticulum. We also discuss the biological mechanisms driving differential FLT3 receptors localization and potential drugs that could alter FLT3 receptors localization for therapeutic purposes. Understanding these mechanisms provides insights into FLT3 receptor biology and may guide the development of novel treatment strategies for patients with FLT3-mutated AML.
Song et al. (Thu,) studied this question.