A team from the Heinrich-Pette Institute (Hamburg, Germany) have discovered that the transcription factor RUNX1, which has known tumor-suppressor function, can actually induce acute myeloid leukemia (AML) in mice with mutations in the gene FLT3. These findings could be utilized to enhance current therapeutic approaches.
Internal tandem duplications (ITDs) in FLT3, which encodes for a cell tyrosine kinase, are one of the most common mutations seen in AML patients and are associated with myeloproliferation and poor prognosis. Paradoxically, it has been reported that samples from AML patients with FLT3-ITD express high levels of RUNX1, a transcription factor with tumor-suppressor functions.
The study, published recently in the Journal of Experimental Medicine, therefore aimed to investigate this phenomenon. The team, led by Carl Stocking (Heinrich-Pette Institute), demonstrated that reducing RUNX1 levels attenuated the ability of human FLT3-ITD cells to form tumors when injected into a mouse model. In addition, the researchers observed that elevated RUNX1 induced AML under the same circumstances.
The group looked into the mechanism behind these findings and discovered that FLT3-ITD cells are highly proliferative, but this is alone not enough to induce AML. However, mutant FLT3 appears to stabilize RUNX1 via phosphorylation, allowing RUNX1 to partially block white blood cell differentiation through interaction with additional transcription factors, allowing myeloproliferation and thus giving rise to AML.
This study has elucidated the unanticipated function of RUNX1 in AML, and the team suggest that inhibiting this activity could lead to better therapeutics for some AML patients, enhancing current approaches based on FLT3 mutations.
Stocking concluded: “Therapies that can reverse this differentiation block may offer significant therapeutic efficacy in AML patients with FLT3 mutations. Ablating RUNX1 is toxic to leukemic cells but not to normal hematopoietic stem cells, so inhibiting RUNX1 may be a promising target in combination with FLT3 inhibitors.”