Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder arising in the hematopoietic progenitors of the myeloid pathway or from naïve multipotent stem cells. The pathogenesis of the disease manifests as deregulation of differentiation pathways (caused by mutations in genes involved in haematopoiesis, such as the mixed-lineage leukaemia (MLL) gene), and a subsequent increase in cellular proliferative capacity (due to mutations in signal transduction pathway genes such as FLT3 and RAS, which may cooperate with MLL mutations). Cytarabine chemotherapy is the gold standard of treatment, however toxicity and poor long-term disease-free survival has led to an urgent need to develop new therapies.
We utilised a novel Tet-induced, retrovirally transduced mouse model that co-expresses the AML fusion protein MLL-AF9 simultaneously with either FLT3-ITD or NRASG12D. As the system allows for the selective de-induction of MLL-AF9, FLT3-ITD or NRASG12D, we aim to use this system to phenocopy drug action, ultimately providing the basis for novel combination therapies.
Our data shows that genetic de-induction of NRASG12D and FLT3-ITD leads to rapid cell death, and reduced cell number within 1 day. In contrast, de-induction of MLL-AF9 led to terminal differentiation in myeloblastic cells to mature murine neutrophils and subsequent cell death after 4 days, suggesting that NRASG12D and FLT3-ITD provide a survival advantage to leukemic cells, while MLL-AF9 blocks differentiation along the myeloid lineage.
These findings provide the pre-clinical basis for targeting NRASG12D and FLT3-ITD mutations therapeutically, in combination with other therapies targeting the AML genome. By elucidating the most effective therapeutic regimens that can ultimately be translated to the clinic, and genomically identifying mutation-relevant drug targets, we hope to expand the repertoire of therapeutic strategies available to clinicians in the treatment of this disease.