Signaling by FLT3 ITD and TKD mutants

At lower frequency, FLT3 is subject to activating point mutations (~7% of AML cases). These mutations tend to cluster in the TKD, with mutation of the activation loop residue D835 and the gatekeeper F691 residue the most common sites (Griffin et al, 2001; Jiang et al, 2004; reviewed in Kazi and Roonstrand, 2019).

FLT3 ITD and TKD mutants support cellular transformation through activation of downstream signaling pathways such as the MAP kinase, PI3K/AKT and STAT5 cascades. There is some debate about the extent to which the pathways activated by the ITD and TKD mutants are distinct, with some evidence that STAT5 signaling, in particular, is more characteristic of FLT3 ITD activation (Hayakawa et al, 2000; Choudhary et al, 2005; Grundler et al, 2005; Choudhary et al, 2007; Yoshimoto et al, 2009; Leischner et al, 2012; Janke et al, 2014; Marhall et al, 2018; reviewed in Chan, 2011; Kazi and Roonstrand, 2019).