Fig. 6: Proposed model for the cooperation of FLT3-ITD and p53 haploinsufficiency or loss, and combined therapy.

The cooperation of FLT3-ITD and p53 haploinsufficiency or loss synergistically induced the downregulation of Lin28a and the upregulation of Htra3, which led to increased proliferation, the inhibition of differentiation and apoptosis, and leukemia development. Htra3 is likely a central mediator, through inhibition of apoptosis and enhancement of proliferation [48]. Moreover, Htra3 also enhanced the inhibition of differentiation by Lin28a. Of note, Htra3 expression in normal HSCs/HPCs is not increased and similar as other mature blood cells (http://servers.binf.ku.dk/bloodspot/?gene). Proteasome inhibitors induced the cell death of FLT3-ITD-positive AML cells through the autophagy of FLT3-ITD and in part the activation of the p53 pathway [47]. Thus, cells with p53 loss can still be sensitive to proteasome inhibitor. AXL can positively regulate the constitutive activation of FLT3-ITD [34], whereas the inhibition of FLT3-ITD by FLT3 inhibitors can induce increased expression/activation of AXL (Fig. 5b), which might induce resistance to FLT3 inhibitors. The overexpression of AXL has been shown to mediate resistance to other kinase inhibitors [49].