ABSTRACT

Recent advances in the study of clonal evolution and step-wise acquisition of mutations during cancer development have revealed that initiating mutations can occur in a pre-malignant state and drastically increase cancer risk. However, options for preventative treatment with targeted therapy that could eradicate pre-malignant clones before they give rise to disease are lacking. Acute myeloid leukemia (AML) is an attractive model system for pre-treatment as it is often preceded by a state of clonal hematopoiesis or myelodysplastic syndrome. Leukemia initiating mutations such as DNMT3a mutations are usually not sufficient for AML development but require co-occurring mutations such as NPM1c. Recent reports suggest that NPM1c mutations can be detected in a premalignant state such as MDS and may act as an indicator of progression to AML. We used a Dnmt3a/Npm1c mutant knock-in mouse model to identify the leukemia initiating population and generate pre-leukemic clones from myeloid progenitor cells. Our data show that Npm1c expression induces a stem cell gene expression program which allows myeloid progenitors to self-renew and engraft long-term before giving rise to leukemia. These pre-leukemic clones could be eradicated by interfering with their aberrant self-renewal properties using the novel orally bioavailable Menin-MLL interaction inhibitor VTP-50469. Furthermore, Menin-MLL inhibition showed high efficacy in eradicating human NPM1c AML cells in PDX models of primary and relapse NPM1c leukemias. These studies suggest it may be possible to prevent AML development in high-risk populations by targeting chromatin associated complexes to reverse preleukemic self-renewal and that the same approaches can be used to treat fully developed disease.