Protein Thought to Prevent Leukemia May Actually Promote Cancer Spread
Protein once thought to suppress tumors in acute myeloid leukemia may instead promote the disease.
A tumor-suppressing protein previously believed to prevent acute myeloid leukemia (AML) was recently found to potentially promote a deadly form of the cancer, according to a new study published by The Journal of Experimental Medicine.
The study authors suggest that targeting the FLT3 signaling protein may be a treatment option for AML that is worth exploring in further studies.
AML is characterized by the proliferation of hematopoietic stem cells in the bone marrow, and their inability to mature into white blood cells. This type of cancer is linked to more than 1% of cancer-related deaths in the United States each year.
AML is typically the result of a number of gene mutations. A common mutation is the gene responsible for encoding the cell surface signaling protein FLT3. Patients with this mutation historically have low rates of survival, according to the study.
While mutated FLT3 can increase cell proliferation, experiments in mice models show that the mutation is not responsible for blocking white cell differentiation, and promotes AML on its own. There are other factors involved, but it was previously unknown.
In the study, the investigators found that patients with a mutant form of FLT3 were also seen to have increased levels of the RUNX1 transcription factor.
"This was unexpected because up to 20 percent of AML patients carry mutations that inactivate RUNX1, which is generally considered to be a tumor suppressor that prevents the formation of leukemias," said researcher Carol Stocking, PhD.
The study authors discovered that reducing RUNX1 levels weakened the ability of human AML cells to create tumors when injected into mice models. However, increased RUNX1 levels plus mutant FLT3 was observed to induce AML.
Mouse hematopoietic stem cells that expressed mutant FLT3 were found to be highly proliferative. These cells, in addition to the expression of RUNX1, blocked white blood cell differentiation and resulted in AML development, according to the study.
Mutant FLT3 was able to stabilize and activate RUNX1 through advancing the phosphorylation of RUNX1. Then, RUNX1 blocks differentiation through inducing the Hhex transcription factor.
Hematopoietic stem cells that expressed Hhex and mutant FLT3 also induced AML, according to the study.
The investigators hypothesize that RUNX1 may prevent the development of AML, but after being activated by FLT3, it blocks cell differentiation, and aids AML.
"Therapies that can reverse this differentiation block may offer significant therapeutic efficacy in AML patients with FLT3 mutations," Dr Stocking concluded. "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."