FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are common in acute myeloid leukemia (AML) and are associated with a high risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) frequently include myeloid differentiation of the FLT3-ITD clone in nearly half of patients, though the underlying mechanism remains unclear. Using a proteomic-based screen, we identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this differentiation effect. FLT3i downregulated EZH2 protein levels and reduced PRC2 activity on H3K27me3. Interestingly, FLT3-ITD mutations and EZH2 loss-of-function mutations are mutually exclusive in human AML.

In murine models of FLT3-ITD AML, FLT3i enhanced myeloid maturation while decreasing stem and progenitor cell populations. Combining EZH1/2 inhibitors with FLT3i further promoted terminal differentiation of leukemic cells and significantly reduced leukemic burden. These findings indicate that FLT3 inhibition diminishes EZH2 activity, facilitating myeloid differentiation of FLT3-ITD leukemic cells and providing a mechanistic basis for observed clinical outcomes. Additionally, this study reveals a novel function of FLT3-ITD in maintaining a myeloid stem/progenitor cell state via modulation of PRC2 activity. These results support the exploration Lirametostat of EZH1/2 inhibitors as a therapeutic strategy for FLT3-ITD AML.