Fig. 4.

Mechanisms of novel targeted therapies in AML in later-stage clinical development. A Mutations in TP53 lead to altered conformation of p53 leading to a subtype of AML characterized by treatment resistance, high relapse rates, and poor overall survival. Novel agents such as eprenetapopt are metabolized into MQ which covalently modifies the mutant p53 protein leading to a wild-type-like conformational change and restoration of normal p53 activity [155]. Recent reports have demonstrated that MQ can drive p53-independent cell death through ROS accumulation [156, 157] and ferroptosis [158]. B Leukemic cells can evade immune surveillance by upregulation of CD47, which binds SIRPa; this emits a “don’t eat me signal” to macrophages [163–165]. Antibodies targeting CD47 can block this inhibitory signal and allow for phagocytosis of leukemic cells [165–167]. C Certain types of AML are characterized by mutated NPM1c or oncogenic fusion partners associated with MLL [173, 174, 179]. These lead to complex formation with menin and LEDGF, ultimately resulting in transcriptional activation of leukemia stem cell promoting genes [175–177]. Blocking this pathway with menin inhibitors such as KO-539 or SNDX-5613 can repress this transcriptional program allowing for differentiation of granulocytes [178, 180, 181]. AML Acute myeloid leukemia, MQ Methylene quinuclidinone, ROS Reactive oxidative species, SIRPa Signal regulatory protein alpha, NPM1c Cytoplasmic NPM1 (mutant NPM1), MLL Histone lysine N-methyltransferase 2A (KMT2A), LEDGF Lens epithelium-derived growth factor, MI Menin inhibitor