AML cells
New research indicates that RUNX1, a known tumor suppressor, actually cooperates with internal tandem duplications in the FLT3 receptor tyrosine kinase (FLT3-ITD) to induce acute myeloid leukemia (AML).
Investigators say this discovery suggests that blocking RUNX1 activity will “greatly enhance” current therapeutic approaches using FLT3 inhibitors.
The discovery was published in The Journal of Experimental Medicine.
The research began when investigators noticed that many AML patients with FLT3-ITD also showed increased levels of RUNX1.
“This was unexpected because up to 20% of AML patients carry mutations that inactivate RUNX1, which is generally considered to be a tumor suppressor that prevents the formation of leukemias,” said study author Carol Stocking, PhD, of Heinrich-Pette-Institute-Leibniz Institute for Experimental Virology in Hamburg, Germany.
To investigate this finding, she and her colleagues injected mice with human AML cells expressing FLT3-ITD. The team found that reducing RUNX1 levels attenuated the cells’ ability to form tumors, but elevated RUNX1 levels worked with FLT3-ITD to induce AML.
Mouse hematopoietic stem cells expressing FLT3-ITD were highly proliferative, and co-expression of RUNX1 blocked their differentiation, allowing them to give rise to AML.
Mutant FLT3 appears to stabilize and activate RUNX1 by promoting the transcription factor’s phosphorylation. Active RUNX1 then blocks differentiation, at least in part, by upregulation of another transcription factor, Hhex.
The investigators found that hematopoietic stem cells expressing both Hhex and FLT3-ITD gave rise to AML.
RUNX1 may therefore suppress the initiation of AML but, after being activated by mutant FLT3, block differentiation and promote tumor development.
“Therapies that can reverse this differentiation block may offer significant therapeutic efficacy in AML patients with FLT3 mutations,” Dr Stocking said. “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.”
