Figure 1.

Proposed Mechanisms of Inhibiting Menin. KMT2Ar fusion proteins bind menin and lead to a stereotyped gene profile expression which includes HOX family genes and MEIS1 leading to a leukemia stem cell like state. The menin inhibitors disrupt binding to menin reducing this gene expression and leading to cell differentiation. FLT3 expression is regulated by upstream factors including MEIS1. Mutated NPM1 also up-regulates the expression of HOXA9 and MEIS1 possibly by cytoplasmic sequestration of transcriptional regulators (such as HEXIM1) which normally inhibit components of KMT2Ar fusion protein complexes.